Flavonoid Derivatives with GABAA Receptor Activity and Methods of Use

Abstract

GABA of Formula I A Provided herein are R positive modulator compounds and the method of using these compounds for the treatment of anxiety, distress and / or alcohol use disorder.In certain embodiments, the compounds are stable and effective flavonoid derivatives that do not show negative side effects when administered in association with alcohol consumption. TIFF2024538721000062.tif106170

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 253,341, filed October 7, 2021, entitled "FLAVONOID DERIVATIVES WITH GABAA RECEPTOR ACTIVITY AND METHODS OF USE," the entire contents of which are incorporated by reference herein. [Background technology]

[0002] background Benzodiazepines (BZDs) are GABA A It is a class of R-positive modulators and the most commonly prescribed acute anxiolytic, with an estimated 5.2% of the population actively prescribed one or more BZDs. Although BZDs are the standard treatment for acute alcohol withdrawal, their outpatient use is risky for individuals with a history of alcohol use disorder.

[0003] BZDs are highly addictive and abuse is common. Although the use of BZDs rarely results in fatal overdoses when taken alone, BZDs become more toxic when combined with other CNS depressants, such as ethanol. The primary danger of BZDs is the synergistic and additive effects when combined with ethanol. Thus, GABA A Although R-positive modulators have shown significant utility and efficacy as acute anxiolytics, their use is limited by potential toxicity when combined with ethanol and can result in expensive hospitalizations and deaths from overdose. Another major problem is that prescribers often do not know whether patients are being honest about their alcohol consumption.

[0004] Currently, 70% of the population consumes alcohol. Dihydromyricetin (DHM), a natural flavonoid, is a GABAA DHM is a GABA R positive allosteric modulator that has been shown to reduce the intoxicating effects of ethanol in rats and mice and is currently available as a dietary supplement. This makes it a safer alternative to DHM, which does not have the ethanol potentiating effects. A DHM holds promise for the development of R PAMs. However, it lacks the drug-like properties and therefore insufficient CNS bioavailability required for reliable translation into clinical efficacy.

[0005] Therefore, GABA A There is an urgent need for clinically effective compounds that are R positive modulators and do not exhibit the enhanced side effects associated with ethanol. The present disclosure addresses this need. Summary of the Invention

[0006] overview In one aspect, there is provided a compound of formula I, or a salt, solvate, tautomer, enantiomer, diastereoisomer, and / or isotopically labeled derivative thereof: TIFF2024538721000002.tif35128 formula, TIFF2024538721000003.tif2128 is independently a single or double bond in each occurrence, and the XC* and GC* bonds are If the XC* bond is a double bond, The GC* bond is a single bond, and X is N, or If the XC* bond is a single bond, The GC* bond is a single or double bond, and X is O, NR, or S Selected to be; Each occurrence of Y is independently R, F, Cl, Br, I, OR, CN, NO2, N(R)2, SR, S(=O)R, SF3, SF5, S(=O)2R, S(=O)2N(R)2, P(=O)OH2, P(=O)OR2, C(=O)R, C(=O)OR, C(=O)N(R)2, OC(=O)R, OC(=O)N(R)2, C3~10 Heterocycloalkyl, and C 5~10 is heteroaryl; G is C or N, If G is N or the GC* bond is a double bond, Z 2 and R 2 does not exist; A is C 6~10 Aryl or C 5~10 heteroaryl, each of which is optionally substituted with 1 to 5 substituents independently selected from the group consisting of R, F, Cl, Br, I, OR, CN, NO2, N(R)2, SR, S(=O)R, SF3, SF5, S(=O)2R, S(=O)2N(R)2, P(=O)OH2, P(=O)OR2, C(=O)R, C(=O)OR, C(=O)N(R)2, OC(=O)R, and OC(=O)N(R)2; Z 1 and Z 2 is independently at each occurrence O, CH2, CHF, or CF2; R 1 and R 2 is independently OR, SR, or R in each occurrence; Or, -(Z 1 ) n1 -R 1 is H, Or, -(Z 2 ) n2 -R 2 is H, Each occurrence of R is hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~8 Cycloalkyl, C 3~8 Cycloalkenyl, and C 3~8 independently selected from the group consisting of halocycloalkyl; n is 1, 2, 3, 4, or 5; n1 is 1, 2, or 3; n2 is 1, 2, or 3.

[0007] In certain embodiments, the compounds of formula I, including pharmaceutical compositions of the compounds of formula I, are useful in treating, ameliorating, and / or preventing alcohol use disorder (AUD) in a subject in need thereof. [Brief description of the drawings]

[0008] The drawings illustrate generally, by way of example, but not by way of limitation, various aspects of the present application.

[0009] [Figure 1] The structure of DHM (dihydromyricetin) is shown. [Figure 2A] Cryo-EM structure of diazepam (valium) in the BZD binding site (PDB: 6X3X). His102 interactions are associated with α1 selectivity. [Figure 2B] The cryo-EM structure of flumazenil in the BZD binding site (PDB: 6T6U) showing the lowest energy conformation of DHM. [Figure 3A] The docking pose of dihydromyricetin is shown. [Figure 3B] 1 shows overlap of docking results for dihydromyricetin and myricetin. [Figure 4A] 1 shows the docking pose of compound of formula I (C1). [Figure 4B] 1 shows the overlap of the docked conformations of DHM and compound of formula I (C1). [Figure 4C] 1 shows the overlap of the docked conformations of 6-bromoflavone and compound of formula I (C1). [Diagram 5] Figures 5A-B show a comparison of concentration-response curves representing the reported extrapolated EC50 value of EC2-118 (Figure 5B) with that of allopregnanolone, a full GABAAR PAM and GABAAR agonist (Figure 5A). [Figure 6] HPLC-UV-MS / MS analysis of EC2-118. [Figure 7]This shows the movement of rats during the open field test. Increased time in the open arms indicates anxiolytic activity. We observed that at a dose of 3.95 mg / kg, rats spent much more time exploring the open arms, indicating a significant reduction in anxiety compared to the vehicle group in the assay. The purple line shows the movement of rats. [Figure 8] Rotarod test with EC2-118 at 3.95 mg / kg and 12.5 mg / kg IP compared to vehicle control. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] Detailed Description Reference will now be made in detail to certain aspects of the disclosed subject matter. While the disclosed subject matter will be described in the context of numbered claims, it will be understood that the subject matter illustrated is not intended to limit the scope of the claims to the subject matter disclosed.

[0011] Throughout this document, values ​​expressed in the form of ranges should be interpreted flexibly to include not only the numerical values ​​expressly set forth as the limits of the range, but also all individual numerical values ​​or subranges subsumed within the range, as if each numerical value and subrange were expressly set forth. For example, the range "about 0.1% to about 5%" or "about 0.1% to 5%" should be interpreted to include not only about 0.1% to about 5%, but also the individual values ​​(e.g., 1%, 2%, 3%, and 4%) and subranges (e.g., 0.1% to 0.5%, 1.1% to 2.2%, 3.3% to 4.4%) within the indicated range. Unless otherwise indicated, the description "about X to Y" has the same meaning as "about X to about Y". Similarly, unless otherwise indicated, the description "about X, Y, or about Z" has the same meaning as "about X, about Y, or about Z".

[0012] In this document, the terms "a", "an", or "the" are used to include one or more, unless the context clearly indicates otherwise. The term "or" is used to mean a non-exclusive "or", unless otherwise indicated. The statements "at least one of A and B" or "at least one of A or B" have the same meaning as "A, B, or A and B". Furthermore, any words or terms used herein and not defined elsewhere should be understood to be for descriptive purposes only and not for limiting purposes. Any use of section headings is intended to aid in the reading of this document and should not be construed as limiting. Information associated with a section heading may occur within or outside the section. All publications, patents, and patent documents mentioned in this document are incorporated herein by reference in their entirety, as if each was incorporated by reference individually.

[0013] In the methods described herein, acts may be performed in any order unless a chronological or operational order is explicitly recited. Moreover, certain acts may be performed simultaneously unless the express language of the claim requires that they must be performed separately. For example, a claimed act of performing X and a claimed act of performing Y may be performed simultaneously in one operation, and the resulting process is within the literal scope of the claimed process.

[0014] definition The term "about" as used herein allows for a variability of a value or range, for example, within 10%, within 5%, or within 1% of a stated value or a stated range limit, and includes the exact value or range stated.

[0015] As used herein, the term "substantially" means "a majority of" or "mostly," similarly meaning at least about 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 99.99%, or at least about 99.999% or more, or 100%. The term "substantially free" as used herein can mean completely free or insignificant, such that the amount of material present does not affect the material properties of a composition containing the material, and thus the material is from about 0% to about 5%, or from about 0% to about 1%, or not more than about 5%, or less than about 4.5%, equal to, or greater than about 4.5%, or not more than 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.01, or not more than about 0.001% by weight of the composition. The term "substantially free" can mean having an insignificant amount, such that a material is between about 0% and about 5%, or between about 0% and about 1%, or less than about 5%, or less than about 4.5%, equal to, or greater than about 4.5%, or less than 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.01, or about 0.001% or less by weight, or about 0%.

[0016] The term "organic group" as used herein means any carbon-containing functional group. Examples include oxygen-containing groups such as alkoxy groups, aryloxy groups, aralkyloxy groups, and oxo (carbonyl) groups; carboxyl groups, including carboxylic acids, carboxylates, and esters; sulfur-containing groups such as alkylsulfide groups and arylsulfide groups; and other heteroatom-containing groups. Non-limiting examples of organic groups include OR, OOR, OC(O)N(R), CN, CF, OCF, R, C(O), methylenedioxy, ethylenedioxy, N(R), SR, SOR, SO, SO, N(R), SO, C(O)R, C(O)C(O)R, C(O)CHC(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R), OC(O)N(R), C(S)N(R), (CH) 0~2 N(R)C(O)R, (CH2) 0~2 These include N(R)N(R), N(R)N(R)C(O)R, N(R)N(R)C(O)OR, N(R)N(R)CON(R), N(R)SOR, N(R)SON(R), N(R)C(O)OR, N(R)C(O)R, N(R)C(S)R, N(R)C(O)N(R), N(R)C(S)N(R), N(COR)COR, N(OR)R, C(=NH)N(R), C(O)N(OR)R, and / or C(=NOR)R, where R can be hydrogen (in instances containing other carbon atoms) or a carbon-based moiety, which may be substituted or unsubstituted.

[0017] The term "substituted" as used herein with respect to a molecule or organic group as defined herein means that one or more hydrogen atoms contained therein are replaced with one or more non-hydrogen atoms. The term "functional group" or "substituent" as used herein means a group that can or does substitute on a molecule or organic group. Examples of substituents or functional groups include, but are not limited to, halogens (e.g., F, Cl, Br, and I); oxygen atoms in groups such as hydroxy, alkoxy, aryloxy, aralkyloxy, oxo(carbonyl), carboxylic acid, carboxylate, and carboxylate ester; sulfur atoms in thiol, alkyl and aryl sulfide, sulfoxide, sulfone, sulfonyl, and sulfonamide groups; nitrogen atoms in groups such as amine, hydroxylamine, nitrile, nitro, N-oxide, hydrazide, azide, and enamine; and other heteroatoms in various other groups. Non-limiting examples of substituents that may be attached to a substituted carbon atom (or other atom) include F, Cl, Br, I, OR, OC(O)N(R), CN, NO, NO, ONO, azido, CF, OCF, R, O(oxo), S(thiono), C(O), S(O), methylenedioxy, ethylenedioxy, N(R), SR, SOR, SO, SO, N(R), SO, R, C(O)R, C(O)C(O)R, C(O)CHC(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R), OC(O)N(R), C(S)N(R), (CH) 0~2 N(R)C(O)R, (CH2) 0~2N(R)N(R)2, N(R)N(R)C(O)R, N(R)N(R)C(O)OR, N(R)N(R)CON(R)2, N(R)SO2R, N(R)SO2N(R)2, N(R)C(O)OR, N(R )C(O)R, N(R)C(S)R, N(R)C(O)N(R)2, N(R)C(S)N(R)2, N(COR)COR, N(OR)R, C(=NH)N(R)2, C(O)N(OR)R, and C(=N OR)R, where R can be hydrogen or a carbon-based moiety, e.g., R can be hydrogen, alkyl, acyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, or heteroarylalkyl, or two R groups attached to a nitrogen atom or adjacent nitrogen atoms can be taken together with one or more of the nitrogen atoms to form a heterocyclyl.

[0018] The term "alkyl" as used herein refers to straight-chain and branched alkyl groups, as well as cycloalkyl groups, having 1 to 40 carbon atoms, 1 to about 20 carbon atoms, 1 to 12 carbons, or in some embodiments, 1 to 8 carbon atoms. Examples of straight-chain alkyl groups include groups having 1 to 8 carbon atoms, such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl. Examples of branched alkyl groups include, but are not limited to, isopropyl, isobutyl, sec-butyl, t-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl. The term "alkyl" as used herein includes n-alkyl, isoalkyl, and anteisoalkyl groups, as well as other branched forms of alkyl. Representative substituted alkyl groups may be substituted one or more times with any of the groups enumerated herein, such as amino groups, hydroxy groups, cyano groups, carboxy groups, nitro groups, thio groups, alkoxy groups, and halogen groups.

[0019] The term "alkenyl" as used herein refers to straight and branched chain and cyclic alkyl groups as defined herein except that at least one double bond exists between two carbon atoms. Thus, alkenyl groups have 2 to 40 carbon atoms, or 2 to about 20 carbon atoms, or 2 to 12 carbon atoms, or in some embodiments, 2 to 8 carbon atoms. Examples include, but are not limited to, vinyl, -CH=C=CCH2, -CH=CH(CH3), -CH=C(CH3)2, -C(CH3)=CH2, -C(CH3)=CH(CH3), -C(CH2CH3)=CH2, cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl, among others.

[0020] The term "alkynyl" as used herein refers to straight and branched chain alkyl groups as defined herein except that at least one triple bond is present between two carbon atoms. Thus, alkynyl groups have 2 to 40 carbon atoms, 2 to about 20 carbon atoms, or 2 to 12 carbons, or in some embodiments, 2 to 8 carbon atoms. Examples include, but are not limited to, -C≡CH, -C≡C(CH3), -C≡C(CH2CH3), -CH2C≡CH, -CH2C≡C(CH3), and -CH2C≡C(CH2CH3), among others.

[0021] The term "acyl" as used herein means a group containing a carbonyl moiety bonded through a carbonyl carbon atom. The carbonyl carbon atom is bonded to a hydrogen forming a "formyl" group or to another carbon atom which may be part of an alkyl group, an aryl group, an aralkyl group, a cycloalkyl group, a cycloalkylalkyl group, a heterocyclyl group, a heterocyclylalkyl group, a heteroaryl group, a heteroarylalkyl group, and the like. The acyl group may contain 0 to about 12, 0 to about 20, or 0 to about 40 additional carbon atoms bonded to the carbonyl group. The acyl group may contain double or triple bonds within the meaning herein. An acryloyl group is an example of an acyl group. An acyl group may contain heteroatoms within the meaning herein. A nicotinoyl group (pyridyl-3-carbonyl) is an example of an acyl group within the meaning herein. Other examples include acetyl, benzoyl, phenylacetyl, pyridylacetyl, cinnamoyl, and acryloyl groups. When the group containing the carbon atom bonded to the carbonyl carbon atom contains a halogen, the group is referred to as a "haloacyl" group. An example is the trifluoroacetyl group.

[0022] The term "cycloalkyl" as used herein refers to cyclic alkyl groups such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, cycloalkyl groups can have from 3 to about 8-12 ring members, while in other embodiments, the number of ring carbon atoms ranges from 3 to 4, 5, 6, or 7. Additionally, cycloalkyl groups include polycyclic cycloalkyl groups such as, but not limited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl, as well as fused rings such as, but not limited to, decalinyl. Cycloalkyl groups also include rings substituted with straight or branched chain alkyl groups as defined herein. Representative substituted cycloalkyl groups can be mono- or more than twice substituted, such as, but not limited to, 2,2-, 2,3-, 2,4-, 2,5-, or 2,6-disubstituted cyclohexyl groups or mono-, di-, or trisubstituted norbornyl or cycloheptyl groups, which may be substituted, for example, with amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups. The term "cycloalkenyl," alone or in combination, refers to a cyclic alkenyl group.

[0023] The term "halocycloalkyl" as used herein refers to a cycloalkyl group in which one or more CH bonds are replaced with CX bonds, where X is an F, Cl, Br, or I atom. If all of these hydrogen atoms are replaced with halogen, the halocycloalkyl is a perhalogenated halocycloalkyl. Examples include, but are not limited to, perfluorinated cycloalkyl. Mixed halogen (two or more halogen atoms) type halocycloalkyl is also contemplated.

[0024] The term "heterocycloalkyl" as used herein refers to a cycloalkyl group in which one or more carbon atoms are replaced by a heteroatom, such as B, O, N, S, or P, and stable oxides of these heteroatoms. Heterocycloalkyl groups may contain one or more degrees of unsaturation, such as carbon-carbon double bonds or carbon-heteroatom double bonds. Heterocycloalkyl groups may be substituted with one or more of any of the substituents described herein.

[0025] The term "aryl" as used herein means a cyclic aromatic hydrocarbon group that does not contain a heteroatom in the ring. Thus, aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenylenyl, anthracenyl, and naphthyl groups. In some embodiments, the aryl group contains about 6 to about 14 carbons in the ring portion of the group. The aryl group may be unsubstituted or substituted as defined herein. Representative substituted aryl groups may be mono- or more than twice substituted, such as, but not limited to, a phenyl group substituted at any one or more of the 2-, 3-, 4-, 5-, or 6-positions of the phenyl ring, or a naphthyl group substituted at any one or more of the 2-8-positions.

[0026] The term "aralkyl" as used herein refers to an alkyl group, as defined herein, in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to an aryl group, as defined herein. Representative aralkyl groups include benzyl and phenylethyl groups, as well as fused (cycloalkylaryl)alkyl groups, such as 4-ethyl-indanyl. An aralkenyl group refers to an alkenyl group, as defined herein, in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to an aryl group, as defined herein.

[0027] The term "heterocyclyl" as used herein refers to aromatic and non-aromatic ring compounds containing three or more ring members, one or more of which are heteroatoms, such as, but not limited to, N, O, and S. Thus, heterocyclyl can be cycloheteroalkyl, or heteroaryl, or any combination thereof, provided it is polycyclic. In some embodiments, heterocyclyl groups contain from 3 to about 20 ring members, while other similar groups have from 3 to about 15 ring members. The term heterocyclyl includes rings in which a CH2 group in the ring is replaced with one or more C=O groups, such as found in cyclic ketones, lactones, and lactams. Examples of heterocyclyl groups containing a C=O group include, but are not limited to, β-propiolactam, γ-butyrolactam, δ-valerolactam, and ε-caprolactam, and the corresponding lactones. A heterocyclyl group referred to as C2-heterocyclyl can be a 5-membered ring with 2 carbon atoms and 3 heteroatoms, a 6-membered ring with 2 carbon atoms and 4 heteroatoms, etc. Similarly, a C4-heterocyclyl can be a 5-membered ring with 1 heteroatom, a 6-membered ring with 2 heteroatoms, etc. The number of carbon atoms and the number of heteroatoms are equal to the total number of ring atoms. A heterocyclyl ring may contain one or more double bonds. A heteroaryl ring is an aspect of a heterocyclyl group. The phrase "heterocyclyl group" includes fused ring species, including species containing fused aromatic and non-aromatic groups. For example, dioxolanyl rings and benzodioxolanyl ring systems (methylenedioxyphenyl ring systems) are both heterocyclyl groups within the meaning herein. The phrase also includes polycyclic ring systems containing heteroatoms, such as, but not limited to, quinuclidyl. A heterocyclyl group can be unsubstituted or substituted as described herein.Heterocyclyl groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, dihydrobenzofuranyl, indolyl, dihydroindolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl. Representative substituted heterocyclyl groups can be groups such as, but not limited to, piperidinyl or quinolinyl groups which are mono- or more than twice substituted, and which are 2-, 3-, 4-, 5- or 6-substituted or disubstituted with groups such as those enumerated herein.

[0028] The term "heteroaryl" as used herein refers to an aromatic ring compound containing five or more ring members, one or more of which are heteroatoms, such as, but not limited to, N, O, and S; for example, a heteroaryl ring can have from 5 to about 8-12 ring members. Heteroaryl groups refer to various heterocyclyl groups that have an aromatic electronic structure. A heteroaryl group referred to as C2-heteroaryl can be a 5-membered ring with 2 carbon atoms and 3 heteroatoms, a 6-membered ring with 2 carbon atoms and 4 heteroatoms, etc. Similarly, a C4-heteroaryl can be a 5-membered ring with 1 heteroatom, a 6-membered ring with 2 heteroatoms, etc. The sum of the number of carbon atoms and the number of heteroatoms equals the total number of ring atoms. C x~y The heterocyclyl ring referred to herein may be any ring containing from "x" to "y" ring members, including all intermediate integers between "x" and "y", and containing one or more heteroatoms as defined herein. x~yIn the ring called C, all non-heteroatom ring members are carbon. x~y The heterocyclyl ring referred to may be a polycyclic ring, for example a bicyclic or tricyclic ring. Heteroaryl groups include, but are not limited to, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. Heteroaryl groups may be unsubstituted or substituted with groups described herein. Representative substituted heteroaryl groups may be substituted one or more times with groups such as those enumerated herein.

[0029] Further examples of aryl and heteroaryl groups include phenyl, biphenyl, indenyl, naphthyl (1-naphthyl, 2-naphthyl), N-hydroxytetrazolyl, N-hydroxytriazolyl, N-hydroxyimidazolyl, anthracenyl (1-anthracenyl, 2-anthracenyl, 3-anthracenyl), thiophenyl (2-thienyl, 3-thienyl), furyl (2-furyl, 3-furyl), indolyl, oxadiazolyl, isoxazolyl, quinazolinyl, fluorenyl, xanthenyl, isoindanyl, benzyl, phenyl ... neshydryl, acridinyl, thiazolyl, pyrrolyl (2-pyrrolyl), pyrazolyl (3-pyrazolyl), imidazolyl (1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), triazolyl (1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl, 1,2,4-triazol-3-yl), oxazolyl (2-oxazolyl, 4-oxazolyl, 5-oxazolyl), thiazolyl (2-thiazolyl, 4-thiazolyl, 5-thiazolyl) , pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl), pyrazinyl, pyridazinyl (3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl), quinolyl (2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl), isoquinolyl (1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl). ), benzo[b]furanyl (2-benzo[b]furanyl, 3-benzo[b]furanyl, 4-benzo[b]furanyl, 5-benzo[b]furanyl, 6-benzo[b]furanyl, 7-benzo[b]furanyl), 2,3-dihydro-benzo[b]furanyl (2-(2,3-dihydro-benzo[b]furanyl), 3-(2,3-dihydro-benzo[b]furanyl), 4-(2,3-dihydro-benzo[b]furanyl), 5-(2,3-dihydro-benzo[b]furanyl), 6-(2,3-dihydro-benzo[b]furanyl), 7-(2,3-Dihydro-benzo[b]furanyl), benzo[b]thiophenyl (2-benzo[b]thiophenyl, 3-benzo[b]thiophenyl, 4-benzo[b]thiophenyl, 5-benzo[b]thiophenyl, 6-benzo[b]thiophenyl, 7-benzo[b]thiophenyl), 2,3-dihydro-benzo[b]thiophenyl, (2-(2,3-dihydro-benzo[b]thiophenyl), 3-(2,3-dihydro-benzo[b]thiophenyl), 4-(2,3-dihydro-benzo[b]thiophenyl), 5-(2,3-dihydro-benzo[b]thiophenyl) nyl), 6-(2,3-dihydro-benzo[b]thiophenyl), 7-(2,3-dihydro-benzo[b]thiophenyl), indolyl (1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), indazole (1-indazolyl, 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl, 7-indazolyl), benzimidazolyl (1-benzimidazolyl, 2-benzimidazolyl, 4-benzimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl, 7-benzimidazolyl), benzothiazolyl (1-benzoxazolyl, 2-benzoxazolyl), benzothiazolyl (1-benzothiazolyl, 2-benzothiazolyl, 4-benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl, 7-benzothiazolyl), carbazolyl (1-carbazolyl, 2-carbazolyl, 3-carbazolyl, 4-carbazolyl), 5H-dibenzo[b,f]azepine (5H-dibenzo[b,f]azepin-1-yl, 5H-dibenzo[b,f]azepin-2-yl, 5 H-dibenzo[b,f]azepin-3-yl, 5H-dibenzo[b,f]azepin-4-yl, 5H-dibenzo[b,f]azepin-5-yl), 10,11-dihydro-5H-dibenzo[b,f]azepine (10,11-dihydro-5H-dibenzo[b,f]azepin-1-yl, 10,11-dihydro-5H-dibenzo[b,f]azepin-2-yl, 10,11-dihydro-5H-dibenzo[b,f]azepin-3-yl, 10,11-dihydro-5H-dibenzo[b,f]azepin-4-yl, 10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl), but are not limited to these.

[0030] The term "heterocyclylalkyl" as used herein means an alkyl group, as defined herein, in which a hydrogen or carbon bond of the alkyl group, as defined herein, is replaced with a bond to a heterocyclyl group, as defined herein. Representative heterocyclylalkyl groups include, but are not limited to, furan-2-ylmethyl, furan-3-ylmethyl, pyridin-3-ylmethyl, tetrahydrofuran-2-ylethyl, and indol-2-ylpropyl.

[0031] The term "heteroarylalkyl," as used herein, means an alkyl group, as defined herein, in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to a heteroaryl group, as defined herein.

[0032] The term "alkoxy" as used herein means an oxygen atom connected to an alkyl group, including cycloalkyl groups, as defined herein. Examples of linear alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, and the like. Examples of branched alkoxy groups include, but are not limited to, isopropoxy, sec-butoxy, tert-butoxy, isopentyloxy, isohexyloxy, and the like. Examples of cyclic alkoxy groups include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like. An alkoxy group can contain about 1 to about 12, about 1 to about 20, or about 1 to about 40 carbon atoms bonded to an oxygen atom, and can further contain double or triple bonds, and can also contain heteroatoms. For example, an allyloxy group or a methoxyethoxy group is also an alkoxy group within the meaning herein, as is a methylenedioxy group in the context in which two adjacent atoms of the structure are replaced therewith.

[0033] The term "amine" as used herein refers to primary, secondary, and tertiary amines, for example having the formula N(group)3, where each group can be independently H, or non-H, such as alkyl, aryl, etc. Amines include, but are not limited to, R-NH2, such as alkylamines, arylamines, alkylarylamines; R2NH, where each R is independently selected, such as dialkylamines, diarylamines, aralkylamines, heterocyclylamines, etc.; and R3N, where each R is independently selected, such as trialkylamines, dialkylarylamines, alkyldiarylamines, triarylamines, etc. The term "amine" as used herein also includes ammonium ions.

[0034] As used herein, the term "amino group" refers to any of the forms -NH2, -NHR, -NR2, -NR3, where each R is independently selected. + and -NR3 which cannot be protonated. + "Amino" refers to the protonated form of each form except for the protonated form of the amino group. Thus, any compound substituted with an amino group can be considered an amine. An "amino group" within the meaning herein can be a primary, secondary, tertiary, or quaternary amino group. An "alkylamino" group includes monoalkylamino groups, dialkylamino groups, and trialkylamino groups.

[0035] The terms "halo," "halogen," or "halide" group as used herein, by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.

[0036] The term "haloalkyl" as used herein includes mono-haloalkyl groups, poly-haloalkyl groups in which all halo atoms may be the same or different, and per-haloalkyl groups in which all hydrogen atoms are replaced with halogen atoms such as fluoro. Examples of haloalkyl include trifluoromethyl, 1,1-dichloroethyl, 1,2-dichloroethyl, 1,3-dibromo-3,3-difluoropropyl, perfluorobutyl, and the like.

[0037] As used herein, the term "solvent" refers to a liquid that can dissolve a solid, liquid, or gas. Non-limiting examples of solvents include silicones, organic compounds, water, alcohols, ionic liquids, and supercritical fluids.

[0038] As used herein, the term "independently selected from" means that the groups referenced are the same, different, or a mixture thereof, unless the context clearly indicates otherwise. Thus, based on this definition, "X 1 , X 2 , and X 3 is independently selected from the noble gases" is intended to include, for example, 1 , X 2 , and X 3 The situation where all are the same, X 1 , X 2 , and X 3 are all different, X 1 and X 2 is the same but X 3 This would include situations where the first and second vertices are different, and other similar permutations.

[0039] As used herein, the term "room temperature" means a temperature of about 15 to 28°C.

[0040] As used herein, the terms "standard temperature" and "standard pressure" mean 20° C. and 101 kPa.

[0041] The term "composition" or "pharmaceutical composition" as used herein means a mixture of at least one compound described herein and a pharma- ceutical acceptable carrier.The pharmaceutical composition facilitates the administration of the compound to a patient or subject.There are multiple techniques of administering the compound in the art, including but not limited to intravenous administration, oral administration, aerosol administration, parenteral administration, intraocular administration, intrapulmonary administration, and topical administration.

[0042] "Disease" refers to a condition in the health of an animal where the animal is unable to maintain homeostasis and where the animal's health will continue to deteriorate if the disease is not remitted.

[0043] In contrast, a "disorder" in an animal is a health state in which the animal is able to maintain homeostasis, but in which the animal's health state is less favorable than it would be in the absence of the disorder. If left untreated, the disorder does not necessarily cause a further deterioration in the animal's health state.

[0044] As used herein, the terms "effective amount", "pharmaceutical effective amount" and "therapeutically effective amount" refer to a non-toxic but sufficient amount of an agent to obtain a desired biological result. The result may be a reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired change in a biological system. The appropriate therapeutic amount in any individual case can be ascertained by one of ordinary skill in the art using routine experimentation.

[0045] As used herein, the term "efficacy" refers to the maximum effect (E) achieved within an assay. max )

[0046] As used herein, the term "pharmaceutical acceptable" means a material, such as a carrier or diluent, that does not abrogate the biological activity or biological properties of the compound and is relatively non-toxic, i.e., the material can be administered to an individual without causing undesired biological effects or deleterious interactions with any of the components of the composition contained in the composition.

[0047] As used herein, the phrase "pharmacologically acceptable salts" refers to salts of the administered compound prepared from pharma- ceutically acceptable non-toxic acids or bases, including inorganic acids or bases, organic acids or bases, as well as solvates, hydrates, or clathrates thereof.

[0048] Suitable pharma- ceutically acceptable acid addition salts can be prepared from inorganic or organic acids, examples of inorganic acids include hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric (including sulfate and hydrogen sulfate), and phosphoric acid (including hydrogen phosphate and dihydrogen phosphate). Suitable organic acids can be selected from the aliphatic, alicyclic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids, examples of which include formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, maleic acid, malonic acid, saccharic acid, fumaric acid, pyruvic acid, aspartic acid, glutamic acid, benzoic acid, anthranilic acid, 4-hydroxybenzoic acid, phenylacetic acid, mandelic acid, embonic acid (pamoic acid), methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, pantothenic acid, trifluoromethanesulfonic acid, 2-hydroxyethanesulfonic acid, p-toluenesulfonic acid, sulfanilic acid, cyclohexylaminosulfonic acid, stearic acid, alginic acid, β-hydroxybutyric acid, salicylic acid, galactaric acid, and galacturonic acid.

[0049] Suitable pharmaceutically acceptable base addition salts of the compounds described herein include, for example, ammonium salts, metal salts including alkali metal salts, alkaline earth metal salts, and transition metal salts, such as, for example, calcium salts, magnesium salts, potassium salts, sodium salts, and zinc salts. Pharmaceutically acceptable base addition salts also include organic salts made from basic amines, such as, for example, N,N'-dibenzylethylene-diamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine. All of these salts can be prepared from the corresponding compound, for example, by reacting the compound with an appropriate acid or base.

[0050] The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" as used herein means a pharmaceutically acceptable material, composition, or carrier, such as a liquid or solid filler, stabilizer, dispersant, suspending agent, diluent, excipient, thickener, solvent, or encapsulating material, involved in carrying or transporting the compound described herein in or to a patient so that it can perform its intended function. Usually, these constructs are carried or transported from one organ or part of the body to another organ or part of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation containing the compound described herein and not harmful to the patient. Some examples of materials which may serve as pharma- ceutically acceptable carriers include sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; surfactants; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffers; and other non-toxic, compatible substances used in pharmaceutical preparations. As used herein, "pharmaceutically acceptable carrier" includes any coating, antibacterial and antifungal agents, absorption delaying agents, and the like, that are compatible with the activity of the compounds described herein and are physiologically acceptable to the patient. Supplementary active compounds may also be incorporated into the composition. "Pharmaceutically acceptable carrier" may further include pharmaceutically acceptable salts of the compounds described herein.Other additional ingredients that may be included in the pharmaceutical compositions used in the methods or compounds described herein are known in the art and described, for example, in Remington's Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, Pa.), which is incorporated herein by reference.

[0051] The terms "patient," "subject," or "individual" are used interchangeably herein and refer to any animal, or cell thereof, whether in vitro or in situ, amenable to the methods described herein. In non-limiting aspects, the patient, subject, or individual is a human.

[0052] As used herein, the term "efficacy" refers to the half-maximal response (ED 50 ) is meant the dose required to produce

[0053] A "therapeutic" treatment is a treatment administered to a subject who exhibits symptoms of a pathology, with the intent of reducing or eliminating the symptoms.

[0054] The term "treatment" or "treating" as used herein is defined as the application or administration (alone or in combination with another therapeutic agent) of a therapeutic agent, i.e., one or more compounds described herein, to a patient having a condition contemplated herein, or a symptom of a condition contemplated herein, for the purpose of curing, curing, alleviating, mitigating, altering, remedying, ameliorating, improving, or affecting the condition contemplated herein, and / or the symptoms of the condition contemplated herein, or to a tissue or cell line isolated from the patient (e.g., for diagnostic or ex vivo use). These treatments can be specifically tailored or modified based on knowledge gained from the field of pharmacogenomics.

[0055] Reagent abbreviations used herein have the following definitions: TPAP Tetrapropylammonium perruthenate; NMO N-Methylmorpholine-N-oxide; THF tetrahydrofuran; TIPSCl triisopropylsilyl chloride; and DCE dichloroethane.

[0056] Preparation of compounds Compounds of formula I or otherwise described herein can be prepared according to the general schemes described herein, or using synthetic methods known to those skilled in the art. The following examples illustrate non-limiting aspects of the compounds described herein and their preparation.

[0057] In various embodiments, the compound of formula I, or a salt, solvate, tautomer, enantiomer, diastereomer, and / or isotopically labeled derivative thereof, has the following structure: TIFF2024538721000004.tif34128In formula, TIFF2024538721000005.tif2128 is independently a single or double bond in each occurrence, and the XC* and GC* bonds are If the XC* bond is a double bond, The GC* bond is a single bond, and X is N, or If the XC* bond is a single bond, The GC* bond is a single or double bond, and X is O, NR, or S Selected to be; Each occurrence of Y is independently R, F, Cl, Br, I, OR, CN, NO2, N(R)2, SR, S(=O)R, SF3, SF5, S(=O)2R, S(=O)2N(R)2, P(=O)OH2, P(=O)OR2, C(=O)R, C(=O)OR, C(=O)N(R)2, OC(=O)R, OC(=O)N(R)2, C 3~10 Heterocycloalkyl, and C 5~10is heteroaryl; G is C or N, If G is N or the GC* bond is a double bond, Z 2 and R 2 does not exist; A is C 6~10 Aryl or C 5~10 heteroaryl, each of which is optionally substituted with 1 to 5 substituents independently selected from the group consisting of R, F, Cl, Br, I, OR, CN, NO2, N(R)2, SR, S(=O)R, SF3, SF5, S(=O)2R, S(=O)2N(R)2, P(=O)OH2, P(=O)OR2, C(=O)R, C(=O)OR, C(=O)N(R)2, OC(=O)R, and OC(=O)N(R)2; Z 1 and Z 2 is independently at each occurrence O, CH2, CHF, or CF2; R 1 and R 2 is independently OR, SR, or R in each occurrence; Or, -(Z 1 ) n1 -R 1 is H, Or, -(Z 2 ) n2 -R 2 is H, Each occurrence of R is hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~8 Cycloalkyl, C 3~8 Cycloalkenyl, and C 3~8 independently selected from the group consisting of halocycloalkyl; n is 1, 2, 3, 4, or 5; n1 is 1, 2, or 3; n2 is 1, 2, or 3.

[0058] XC* and GC* bonds refer to the bonds between variables X or G, respectively, and the carbons designated with * in the structure of Formula I.

[0059] In various embodiments, the compound of formula I, or a salt, solvate, tautomer, enantiomer, diastereomer, and / or isotopically labeled derivative thereof, has the following structure: TIFF2024538721000006.tif35128In formula, TIFF2024538721000007.tif2128 is independently a single bond or a double bond in each occurrence; Each occurrence of Y is independently R, F, Cl, Br, I, OR, CN, NO2, N(R)2, SR, S(=O)R, SF3, SF5, S(=O)2R, S(=O)2N(R)2, P(=O)OH2, P(=O)OR2, C(=O)R, C(=O)OR, C(=O)N(R)2, OC(=O)R, OC(=O)N(R)2, C 3~10 Heterocycloalkyl, and C 5~10 is heteroaryl; X is O, N, NR, or S; G is C or N, and if G is N, Z 2 and R 2 does not exist; A is C 6~10 Aryl or C 5~10 heteroaryl, each of which is optionally substituted with 1 to 5 substituents independently selected from the group consisting of R, F, Cl, Br, I, OR, CN, NO2, N(R)2, SR, S(=O)R, SF3, SF5, S(=O)2R, S(=O)2N(R)2, P(=O)OH2, P(=O)OR2, C(=O)R, C(=O)OR, C(=O)N(R)2, OC(=O)R, and OC(=O)N(R)2; Z 1 and Z 2 is independently at each occurrence H, O, CH2, CHF, or CF2; R 1 and R 2 each independently is absent, H, OR, SR, or R; Each occurrence of R is hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~8 Cycloalkyl, C 3~8 Cycloalkenyl, and C 3~8 independently selected from the group consisting of halocycloalkyl; n is 1, 2, 3, 4, or 5; n1 is 1, 2, or 3; n2 is 1, 2, or 3.

[0060] In certain embodiments, the compound does not contain an OO bond. In certain embodiments, the compound does not contain an SO bond (e.g., in -SO-). In certain embodiments, the compound does not contain an SS bond. In certain embodiments, the compound does not contain an SSS bond.

[0061] In various embodiments, X is O. In various embodiments, X is S. In various embodiments, X is NR. In various embodiments, X is NH. In various embodiments, G is C. In various embodiments, Z 1 and Z 2 is CH2. In various embodiments, n1 and n2 are 1. In various embodiments, n1 and n2 are 2. In various embodiments, n1 and n2 are 3. In various embodiments, R 1 and R 2 is OH. In various embodiments, A is an optionally substituted phenyl. In various embodiments, A is phenyl or 3-nitrophenyl. In various embodiments, G is N and Z is 1 is H and R 1 does not exist.

[0062] In various embodiments, when A is phenyl, the position of the substituent Q is In TIFF2024538721000008.tif9128, it is not replaced with OH or F.

[0063] In various embodiments, the compound of formula I has the structure It has one of the following: TIFF2024538721000009.tif70147.

[0064] In various embodiments, the compound of formula I has the structure I have one of them: TIFF2024538721000010.tif66158.

[0065] In various embodiments, the rings in the compounds of formula I having one or more Y substituents have the following substitution pattern: TIFF2024538721000011.tif22133.

[0066] The wavy lines represent the remainder of the ring and substituents in compounds of formula I. The wavy lines designated with * are attached to the variable X.

[0067] In various embodiments, the compound of formula I may be any of the following enantiomers: TIFF2024538721000012.tif35128.

[0068] When multiple chiral centers are present in the compound of formula I, the compounds of formulae I-E1 and I-E2 are diastereomers.

[0069] When the carbon to which the A substituent is attached is the only chiral center in the compound of formula I, the exact stereochemical designation of the center (R or S) depends on the definition of the variables in the compound of formula I-E1 or formula I-E2. The enantiomeric purity of the composition may be about 99.5, 99, 98, 97, 96, 95, 94, 93, 92, 91, 90, 85, 80, 75, 70, 65, or 60% or more of formula I-E1, or the enantiomeric purity of the composition may be about 99.5, 99, 98, 97, 96, 95, 94, 93, 92, 91, 90, 85, 80, 75, 70, 65, or 60% or more of formula I-E2. The compound of formula I may exist as a racemic mixture.

[0070] In various embodiments, A is TIFF2024538721000013.tif11128, p is an integer from 1 to 5; Q is selected from the group consisting of F, Cl, Br, I, OR, CN, NO2, N(R)2, SR, S(=O)R, SF3, SF5, S(=O)2R, S(=O)2N(R)2, P(=O)OH2, P(=O)OR2, C(=O)R, C(=O)OR, C(=O)N(R)2, OC(=O)R, and OC(=O)N(R)2, where R is hydrogen, C(=O)R, C(=O)OR, C(=O)N(R), and ... 1~6 Alkyl, C 1~6 Haloalkyl, C 3~8 Cycloalkyl, C 3~8 halocycloalkyl, and combinations thereof. In various embodiments, R in A is H, methyl, ethyl, propyl, or isopropyl.

[0071] In various embodiments, p is 1. In various embodiments, p is 2. In various embodiments, p is 3. In various embodiments, p is 4. In various embodiments, p is 5.

[0072] In various embodiments, A is The file is TIFF2024538721000014.tif55153.

[0073] Any of the A groups described herein can be combined with the compounds of formula I.

[0074] In various embodiments, the compound of formula I is TIFF2024538721000015.tif29156.

[0075] In various embodiments, each Y is R, F, Cl, Br, I, OR, CN, NO2, N(R)2, SR, S(=O)R, SF3, SF5, S(=O)2R, S(=O)2N(R)2, P(=O)OH2, P(=O)OR2, C(=O)R, C(=O)OR, C(=O)N(R)2, OC(=O)R, OC(=O)N(R), C(=O)N(R), C(=O)OH, C(=O)OR, C(=O)R, C(=O)OR, C(=O)N(R), OC(=O)R, C(=O)N(R), ... 3~10 Heterocycloalkyl, and C 5~10heteroaryl, R is independently selected at each occurrence from hydrogen, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~8 Cycloalkyl, C 3~8 halocycloalkyl, or combinations thereof. In various embodiments, R at each occurrence is independently H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, or t-butyl.

[0076] In various embodiments, Y is a halogen (F, Cl, Br, or I). In various embodiments, Y is Br. In various embodiments, the compound of formula I, or a tautomer thereof, is TIFF2024538721000016.tif53132.

[0077] Tautomers of the compounds of formula I include, for example, the following structures: Tautomers of compounds C4 and C5 are included, having the formula: TIFF2024538721000017.tif26140.

[0078] The compounds of formula I may be formulated as pharmaceutical compositions comprising a compound of formula I and at least one pharma- ceutically acceptable carrier or excipient described herein.

[0079] In various embodiments, compounds of formula I may be synthesized according to Schemes 1, 2, 3, and 4.

[0080] TIFF2024538721000018.tif27128Scheme 1: a) NBS, MeOH, oxone, b) RCHO, MeOH, Na2CO3

[0081] TIFF2024538721000019.tif64128 Scheme 2: a) MeOH, KOH, b) KOH, MeOH, c) RCHO, Na2CO3

[0082] TIFF2024538721000020.tif77159a) BF3-OEt2, DCE, 50℃, b) LiBH4, THF, c) 1) TIPSCl, imidazole, DMF, 2) TPAP, NMO, THF, Bu4NF TIFF2024538721000021.tif25161Scheme 3: a) RCHO, base, heat; b) strong base, alkylating agent

[0083] TIFF2024538721000022.tif27155Scheme 4: a) RCHO, base, heat; b) strong base, alkylating agent

[0084] In various embodiments, the compounds of Formula I cross the blood-brain barrier.

[0085] The compounds described herein may have one or more stereocenters, and each stereocenter may independently exist in the (R) or (S) configuration. In certain embodiments, the compounds described herein exist as optically active or racemic forms. It should be understood that the compounds described herein encompass racemates, optically active forms, positional isomers, and stereoisomers, or combinations thereof, that have the therapeutically useful properties described herein. Preparation of optically active forms is accomplished in any suitable manner, including, but not limited to, resolution of racemates by recrystallization techniques, synthesis from optically active starting materials, chiral synthesis, or chromatographic separation using chiral stationary phases. In certain embodiments, a mixture of one or more isomers is utilized as the therapeutic compound described herein. In other embodiments, the compounds described herein include one or more chiral centers. These compounds are prepared by any means, including stereoselective synthesis, enantioselective synthesis, and / or separation of mixtures of enantiomers and / or diastereomers. Resolution of the compounds and their isomers can be achieved by any means, including, but not limited to, chemical processes, enzymatic processes, fractional crystallization, distillation, and chromatography.

[0086] The methods and formulations described herein include the use of N-oxides (if appropriate), crystalline forms (also known as polymorphs), solvates, amorphous phases, and / or pharma- ceutically acceptable salts of compounds having the structures of any of the compounds described herein, as well as metabolites and active metabolites of these compounds that exhibit the same activity. Solvates include solvates with water, ethers (e.g., tetrahydrofuran, methyl tert-butyl ether) or alcohols (e.g., ethanol), acetate esters, and the like. In certain embodiments, the compounds described herein exist in solvated forms with pharma- ceutically acceptable solvents, such as water and ethanol. In other embodiments, the compounds described herein exist in unsolvated forms.

[0087] In certain aspects, the compounds described herein can exist as tautomers, and all tautomers are included within the scope of the compounds presented herein.

[0088] In certain embodiments, the compounds described herein are prepared as prodrugs. "Prodrug" refers to a substance that is converted to the parent drug in vivo. In certain embodiments, upon in vivo administration, the prodrug is chemically converted to the biologically, pharmacologic, or therapeutically active form of the compound. In other embodiments, the prodrug is enzymatically metabolized to the biologically, pharmacologic, or therapeutically active form of the compound by one or more steps or processes.

[0089] In certain embodiments, sites on the aromatic ring moiety of the compounds described herein are susceptible to various metabolic reactions. By incorporating suitable substituents on the aromatic ring structure, this metabolic pathway can be reduced, minimized, or eliminated. In certain embodiments, suitable substituents for reducing or eliminating the susceptibility of the aromatic ring to metabolic reactions are, by way of example only, deuterium, halogen, or alkyl groups.

[0090] The compounds described herein also include isotopically labeled compounds in which one or more atoms are replaced with an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Examples of isotopes suitable for inclusion in the compounds described herein include: 2 H, 3 H, 11 C. 13 C. 14 C. 36 Cl, 18 F, 123 I, 125 I, 13 N, 15 N, 15 O. 17 O. 18 O. 32 P, and 35 In certain embodiments, isotope-labeled compounds are useful in drug distribution studies and / or substrate tissue distribution studies. In other embodiments, substitution with heavy isotopes such as deuterium provides increased metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements). In yet other embodiments, 11 C. 18 F, 15 O, and 13 Substitution with positron emitting isotopes, such as N, is useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically labeled compounds are prepared by any suitable method or process that employs an appropriately isotopically labeled reagent in place of an otherwise non-labeled reagent.

[0091] In certain aspects, the compounds described herein are labeled by other means, including but not limited to the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[0092] The compounds described herein, and other related compounds having different substituents, can be prepared using the techniques and materials described herein and in other publications such as Fieser & Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March, Advanced Organic Chemistry 4 th Ed., (Wiley 1992); Carey & Sundberg, Advanced Organic Chemistry 4th Ed., Vols. A and B (Plenum 2000,2001) and Green & Wuts, Protective Groups in Organic Synthesis 3rd Ed., (Wiley 1999), the disclosures of which are all incorporated by reference. The general methods for the preparation of the compounds described herein are modified by the use of appropriate reagents and conditions to introduce the various moieties found in the formulas shown herein.

[0093] The compounds described herein are synthesized using any suitable procedure starting from compounds available from commercial sources or prepared using the procedures described herein.

[0094] In certain embodiments, reactive functional groups such as hydroxyl, amino, imino, thio, or carboxy groups are protected to avoid their undesired participation in reactions. Protecting groups are used to block some or all reactive moieties to prevent them from participating in chemical reactions until the protecting group is removed. In other embodiments, each protecting group is removable by a different means. The need for differential removal is met by protecting groups that are cleaved under completely different reaction conditions.

[0095] In certain embodiments, the protecting groups are removed by acid, base, reducing conditions (e.g., hydrogenolysis), and / or oxidative conditions. Groups such as trityl, dimethoxytrityl, acetal, and t-butyldimethylsilyl, triisopropylsilyl are acid labile and are used to protect carboxy- and hydroxy-reactive moieties in the presence of Cbz-protected amino groups, which are also hydrogenolysis-removable, and Fmoc-protected amino groups, which are base labile. Carboxylic acid- and hydroxy-reactive moieties are blocked with base-labile groups, such as, but not limited to, methyl, ethyl, and acetyl, in the presence of amines blocked with acid-labile groups, such as t-butyl carbamate, or blocked with carbamates, which are acid- and base-stable, but hydrolytically removable. Silyl groups are also selectively removable by fluoride ions.

[0096] In certain embodiments, carboxylic acid and hydroxy reactive moieties are blocked with hydrolytically removable protecting groups such as benzyl groups, while amine groups capable of hydrogen bonding with acids are blocked with base labile groups such as Fmoc. Carboxylic acid reactive moieties are protected by conversion to simple ester compounds exemplified herein, including conversion to alkyl esters, or are blocked with oxidatively removable protecting groups such as 2,4-dimethoxybenzyl, while concurrent amino groups are blocked with fluoride labile silyl carbamates.

[0097] Allyl blocking groups are useful in the presence of acid and base protecting groups because the former are stable and subsequently removed by metal or pi-acid catalysis. For example, allyl-blocked carboxylic acids are deprotected by palladium catalysis in the presence of acid labile t-butyl carbamate or base labile acetate amine protecting groups. Yet another form of protecting group is a resin to which a compound or intermediate is attached. As long as the residue is attached to the resin, that functional group is blocked and will not react. When released from the resin the functional group becomes available for reaction.

[0098] Typically, blocking / protecting groups may be selected from: TIFF2024538721000023.tif80138

[0099] Other protecting groups, along with detailed descriptions of techniques applicable to the creation and removal of protecting groups, are described in Greene & Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, NY, 1999, and Kocienski, Protective Groups, Thieme Verlag, New York, NY, 1994, the disclosures of which are incorporated herein by reference.

[0100] composition Compositions comprising the compounds described herein include pharmaceutical compositions comprising at least one compound described herein and at least one pharma- ceutically acceptable carrier. In certain embodiments, the compositions are formulated for oral or parenteral administration, such as transdermal, transmucosal (e.g., sublingual, intralingual, buccal (transbuccal), urethral (transurethral), intravaginal (e.g., vaginal and perivaginal), nasal (intranasal), and rectal (rectal), intravesical, intrapulmonary, intraduodenal, intragastric, intrathecal, subcutaneous, intramuscular, intradermal, intraarterial, intravenous, intrabronchial, inhalation, and topical administration.

[0101] Methods of Treatment, Amelioration, and / or Prevention The present disclosure includes methods of treating, ameliorating, and / or preventing alcohol use disorders (AUD) using compounds of formula I. The present disclosure also includes methods of treating, ameliorating, and / or preventing anxiety and distress using compounds of formula I. The present disclosure also includes methods of treating, ameliorating, and / or preventing benzodiazepine physical dependence (also known as anxiolytic use disorder).

[0102] Treatment of AUDs usually involves early withdrawal pharmacotherapy to address the reduction in GABAergic transmission. BZDs are the most commonly prescribed GABAergic A Dihydromyricetin (DHM) is a naturally occurring flavonoid and GABA inhibitor that potentiates respiratory depression and the euphoric effects of alcohol and opiates, which are responsible for many fatal accidents and overdoses. A R PAM / ethanol-induced GABA A R potentiation inhibitor and shows some biological activity for AUD treatment. However, like most flavonoids, DHM lacks drug-like properties and therefore has poor and variable bioavailability.

[0103] Surprisingly and unexpectedly, in various embodiments, a subject who takes a compound of formula I and consumes alcohol (ethanol) does not suffer serious and / or adverse side effects as a result of taking the compound of formula I. In various embodiments, administration of a compound of formula I results in a therapeutically effective concentration of the compound in the brain as a result of the compound crossing the blood-brain barrier (BBB).

[0104] The method described herein comprises administering to the subject a therapeutically effective amount of at least one compound described herein, which may be formulated as a pharmaceutical composition.In various embodiments, the therapeutically effective amount of at least one compound described herein present in the pharmaceutical composition is the only therapeutically active compound in the pharmaceutical composition.In certain embodiments, the method further comprises administering to the subject an additional therapeutic agent that treats AUD and / or anxiety and / or distress.

[0105] In certain embodiments, administration of a compound described herein to a subject allows for the administration of a lower dose of an additional therapeutic agent compared to the dose of the additional therapeutic agent alone required to achieve a similar result in treating AUD, anxiety, or distress in the subject. For example, in certain embodiments, the compound described herein enhances the activity of the additional therapeutic compound, thereby reducing the dose of the additional therapeutic compound to achieve the same effect.

[0106] In certain embodiments, the compounds described herein and the therapeutic agent are administered simultaneously to a subject. In other embodiments, the compounds described herein and the therapeutic agent are co-formulated and administered simultaneously to a subject.

[0107] In certain embodiments, the subject is a mammal. In other embodiments, the mammal is a human.

[0108] Combination therapy The compounds useful in the methods described herein can be used in combination with one or more additional therapeutic agents useful for treating, ameliorating, and / or preventing AUD, anxiety, and / or distress. These additional therapeutic agents can include compounds that are commercially available or available to those skilled in the art by synthesis. These additional therapeutic agents are known to treat or reduce symptoms of AUD or anxiety.

[0109] In various embodiments, synergistic effects are observed when the compounds described herein are administered with one or more additional therapeutic agents or compounds. Synergistic effects can be observed, for example, with sigmoid-E maxThe combination of drugs can be calculated using any suitable method, for example, the concentration-effect curve, the isobologram curve, and the combination index curve, which are useful for evaluating the effect of drug combinations. The corresponding graphs associated with the above-mentioned equations are the concentration-effect curve, the isobologram curve, and the combination index curve, respectively.

[0110] Administration / Dosage / Formulation The dosing regimen may affect what constitutes an effective amount. The therapeutic formulation may be administered prior to or after the onset of AUD, anxiety, or distress in the subject. Additionally, several divided and staggered doses may be administered daily or sequentially, or the dose may be continuously infused or bolus injected. Additionally, the dosage of the therapeutic formulation may be proportionally increased or decreased as required by the therapeutic or prophylactic situation.

[0111] The administration of the compositions described herein to a patient can be performed using known procedures at dosages and for periods of time effective to treat AUD or anxiety in the patient. The effective amount of the therapeutic compound required to achieve a therapeutic effect can vary according to factors such as the current state of the disease or disorder in the patient; the age, sex, and weight of the patient; and the ability of the therapeutic compound to treat AUD or anxiety in the patient. The administration regimen can be adjusted to achieve an optimal therapeutic response. For example, several divided doses may be administered daily, or the dose may be proportionally reduced as required by the therapeutic situation. A non-limiting example of an effective amount range for the therapeutic compounds described herein is about 1-5,000 mg / kg body weight / day. One of skill in the art would be able to consider the relevant factors and make the determination regarding the effective amount of the therapeutic compound without undue experimentation.

[0112] Actual dosage levels of the active ingredients in the pharmaceutical compositions described herein can be varied to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response, desired composition, and desired mode of administration for a particular patient, without being toxic to the patient.

[0113] In particular, the selected dosage level will depend on a variety of factors, including the activity of the particular compound used, the time of administration, the rate of excretion of the compound, the duration of treatment, other drugs, compounds, or materials used in combination with the compound, the age, sex, weight, physical condition, general health, and prior medical history of the patient being treated, and similar factors well known in the medical arts.

[0114] A medical practitioner, such as a physician or veterinarian, having ordinary skill in the art can easily determine and prescribe the effective amount of the required pharmaceutical composition. For example, the physician or veterinarian can start the dosage of the compound described herein used in the pharmaceutical composition at a level lower than that required to obtain the desired therapeutic effect, and gradually increase the dosage until the desired effect is obtained.

[0115] In certain embodiments, it is particularly advantageous to formulate the compound in unit dosage form for ease of administration and uniformity of dosage.As used herein, unit dosage form refers to a physically separate unit suitable as a unit dosage form for the patient to be treated, each unit containing a predetermined amount of therapeutic compound calculated to produce a desired therapeutic effect, combined with a required pharmaceutical vehicle.The unit dosage form of the compound described herein is determined by and directly depends on (a) the unique characteristics of therapeutic compound and the specific therapeutic effect to be achieved, and (b) the limitations inherent in the field of compounding / formulating said therapeutic compound.

[0116] In certain embodiments, the compositions described herein are formulated using one or more pharma- ceutically acceptable excipients or carriers. In certain embodiments, the pharmaceutical compositions described herein comprise a therapeutically effective amount of the compounds described herein and a pharma- ceutically acceptable carrier.

[0117] The carrier can be a solvent or dispersion medium, for example, containing water, ethanol, polyol (for example, glycerin, propylene glycol, and liquid polyethylene glycol, etc.), suitable mixtures thereof, and vegetable oils. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it is preferable to include isotonic agents, for example, sugars, sodium chloride, or polyalcohols such as mannitol and sorbitol, in the composition. Prolonged absorption of the injectable composition can be brought about by including in the composition an agent that delays absorption, for example, aluminum monostearate or gelatin.

[0118] In certain embodiments, the compositions described herein are administered to a patient at a dosing frequency ranging from 1 to 5 or more times per day. In other embodiments, the compositions described herein are administered to a patient at a dosing frequency ranging from, but not limited to, once a day, once every 2 days, once every 3 days to once a week, and once every 2 weeks. Those skilled in the art will appreciate that the dosing frequency of the various combination compositions described herein will vary from individual to individual depending on many factors, including, but not limited to, age, disease or disorder to be treated, sex, general health, and other factors. Thus, administration of the compounds and compositions described herein should not be construed as being limited to any particular dosing regime, and the exact dosing frequency and composition administered to any patient will be determined by the attending physician taking into account all other factors related to the patient.

[0119] The compounds described herein for administration may be administered in doses ranging from about 1 μg to about 10,000 mg, about 20 μg to about 9,500 mg, about 40 μg to about 9,000 mg, about 75 μg to about 8,500 mg, about 150 μg to about 7,500 mg, about 200 μg to about 7,000 mg, about 350 μg to about 6,000 mg, about 500 μg to about 5,000 mg, about 750 μg to about 4,000 mg, about 1 mg to about 3, The range may be from about 1,000 mg, about 10 mg to about 2,500 mg, about 20 mg to about 2,000 mg, about 25 mg to about 1,500 mg, about 30 mg to about 1,000 mg, about 40 mg to about 900 mg, about 50 mg to about 800 mg, about 60 mg to about 750 mg, about 70 mg to about 600 mg, about 80 mg to about 500 mg, and any integer or non-integer unit range therebetween.

[0120] In some embodiments, the dosage of the compounds described herein is from about 1 mg to about 2,500 mg. In some embodiments, the dosage of the compounds described herein used in the compositions described herein is less than about 10,000 mg, or less than about 8,000 mg, or less than about 6,000 mg, or less than about 5,000 mg, or less than about 3,000 mg, or less than about 2,000 mg, or less than about 1,000 mg, or less than about 500 mg, or less than about 200 mg, or less than about 50 mg. Similarly, in some embodiments, the dose of the second compound described herein is less than about 1,000 mg, or less than about 800 mg, or less than about 600 mg, or less than about 500 mg, or less than about 400 mg, or less than about 300 mg, or less than about 200 mg, or less than about 100 mg, or less than about 50 mg, or less than about 40 mg, or less than about 30 mg, or less than about 25 mg, or less than about 20 mg, or less than about 15 mg, or less than about 10 mg, or less than about 5 mg, or less than about 2 mg, or less than about 1 mg, or less than about 0.5 mg, and all integer or non-integer units therebetween.

[0121] In certain embodiments, the compositions described herein are packaged pharmaceutical compositions comprising a container holding a therapeutically effective amount of a compound described herein, alone or in combination with a second agent, and instructions for using the compound to treat, prevent, or reduce one or more symptoms of AUD and / or anxiety in a patient.

[0122] The preparations can be used in admixture with conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carrier substances, suitable for oral, parenteral, nasal, intravenous, subcutaneous, enteral, or any other suitable administration mode known in the art.The pharmaceutical preparations may be sterilized, and if desired, may be mixed with auxiliary substances, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring substances, flavoring substances, and / or aromatic substances.If desired, they may be combined with other effective substances, such as other analgesics.

[0123] The route of administration of any composition described herein includes oral, nasal, rectal, vaginal, parenteral, buccal, sublingual, or topical.The compound used in the composition described herein can be formulated for administration by any suitable route, for example, oral or parenteral administration, for example, transdermal, transmucosal (e.g. sublingual, intralingual, buccal (buccal), urethral (urethral), intravaginal (e.g. vaginal and perivaginal), intranasal (intranasal), and rectal (rectal)), intravesical, intrapulmonary, intraduodenal, intragastric, intrathecal, subcutaneous, intramuscular, intradermal, intraarterial, intravenous, intrabronchial, inhalation, and topical administration.

[0124] Suitable compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gel capsules, nanocapsules, troches, dispersions, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, magmas, electuaries, creams, pastes, plasters, lotions, discs, suppositories, liquid sprays for nasal or oral administration, dry powder or aerosol formulations for inhalation, compositions and formulations for intravesical administration, etc. It should be understood that the formulations and compositions described herein are not limited to the specific formulations and compositions described herein.

[0125] Oral route For oral application, tablets, dragees, liquids, drops, suppositories, or capsules, caplets, and gel capsules are particularly suitable. Compositions intended for oral use can be prepared according to any method known in the art, and these compositions may contain one or more substances selected from the group consisting of inert and non-toxic pharmaceutical excipients suitable for the manufacture of tablets. These excipients include, for example, inert diluents such as lactose; granulating and disintegrating agents such as cornstarch; binding agents such as starch; and lubricants such as magnesium stearate. Tablets may be uncoated or may be coated by known techniques to improve appearance or to delay the release of the active ingredient. Oral preparations may be presented as hard gelatin capsules in which the active ingredient and inert diluents are mixed.

[0126] For oral administration, the compounds described herein may be in the form of tablets or capsules prepared by conventional means with pharma- ceutically acceptable excipients, such as binders (e.g., polyvinylpyrrolidone, hydroxypropylcellulose, or hydroxypropylmethylcellulose); fillers (e.g., corn starch, lactose, microcrystalline cellulose, or calcium phosphate); lubricants (e.g., magnesium stearate, talc, or silica); disintegrants (e.g., sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate). If desired, tablets can be coated using suitable methods and coating materials, such as the OPADRY™ film coating system available from Colorcon, West Point, Pennsylvania (e.g., OPADRY™ OY type, OYC type, organic enteric OY-P type, aqueous enteric OY-A type, OY-PM type, and OPADRY™ White, 32K18400). Liquid formulations for oral administration can be in the form of solutions, syrups, or suspensions. Liquid preparations can be prepared in a conventional manner with pharma- ceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methylcellulose, or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters, or ethyl alcohol); and preservatives (e.g., methyl or propyl p-hydroxybenzoate or sorbic acid).

[0127] The compositions described herein can be prepared, packaged, or sold in a formulation suitable for oral or buccal administration. Tablets containing the compounds described herein can be made, for example, by compressing or molding the active ingredient, optionally with one or more additional ingredients. Compressed tablets can be prepared by compressing the active ingredient in a free-flowing form, such as a powdered or granular preparation, optionally mixed with one or more of a binder, lubricant, excipient, surfactant, and dispersant, in a suitable device. Molded tablets can be prepared by molding a mixture of the active ingredient, a pharmaceutically acceptable carrier, and at least enough liquid to moisten the mixture in a suitable device. Pharmaceutically acceptable excipients used in tablet manufacture include, but are not limited to, inert diluents, granulating and disintegrating agents, dispersing agents, surfactants, disintegrating agents, binders, and lubricants.

[0128] Suitable dispersing agents include, but are not limited to, potato starch, sodium starch glycolate, poloxamer 407, or poloxamer 188. The dispersing agent or agents may be present in the composition in an amount of from about 0.01% w / w to about 90% w / w, each individually, by weight of the dosage form. The dispersing agent or agents may be present in the composition in an amount of greater than, greater than, or less than about 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% w / w, each individually, by weight of the dosage form.

[0129] The surfactant may be a cationic surfactant, an anionic surfactant, or a nonionic surfactant, or a combination thereof. Suitable surfactants include behentrimonium chloride, benzalkonium chloride, benzethonium chloride, benzododecinium bromide, carbetopendecinium bromide, cetalkonium chloride, cetrimonium bromide, cetrimonium chloride, cetylpyridine chloride, didecyldimethylammonium chloride, dimethyldioctadecylammonium bromide, dimethyldioctadecylammonium chloride, domiphen bromide, lauryl methyl gluceth-10. Hydroxypropyldimonium chloride, tetramethylammonium hydroxide, thonzonium bromide, stearalkonium chloride, octenidine dihydrochloride, olaflur, N-oleyl-1,3-propanediamine, 2-acrylamido-2-methylpropanesulfonic acid, alkylbenzenesulfonate, ammonium lauryl sulfate, ammonium perfluorononanoate, docusate, disodium cocoamphodiacetate, magnesium laureth sulfate, perfluorobutanesulfonic acid, perfluorononanoic acid, perfluorooctane sulfonic acid, perfluorooctanoic acid, potassium lauryl sulfate, sodium alkyl sulfate, sodium dodecyl sulfate, sodium laurate, sodium laureth sulfate, sodium lauroyl sarcosinate , sodium myreth sulfate, sodium nonanoyloxybenzenesulfonate, sodium pareth sulfate, sodium stearate, sodium sulfosuccinate, cetomacrogol 1000, cetostearyl alcohol, cetyl alcohol, cocamide diethanolamine, cocamide monoethanolamine, decyl glucoside, decyl polyglucose, glyceryl monostearate, octylphenoxypolyethoxyethanol CA-630, isoceteth-20, lauryl glucoside, octylphenoxypolyethoxyethanol P-40, nonoxynol-9, nonoxynol, nonylphenoxypolyethoxyethanol (NP-40), octaethylene glycol monododecyl ether, N-octylExamples of surfactants include, but are not limited to, β-D-thioglucopyranoside, octyl glucoside, oleyl alcohol, PEG-10 sunflower glyceride, pentaethylene glycol monododecyl ether, polidocanol, poloxamer, poloxamer 407, polyethoxylated tallowamine, polyglyceryl polyricinoleate, polysorbate, polysorbate 20, polysorbate 80, sorbitan, sorbitan monolaurate, sorbitan monostearate, sorbitan tristearate, stearyl alcohol, surfactin, Triton X-100, and Tween 80. The one or more surfactants may each be present in the composition individually in an amount of about 0.01% w / w to about 90% w / w by weight of the dosage form. One or more surfactants may be present in the composition in an amount of greater than, greater than, or less than about 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% w / w by weight of the dosage form.

[0130] Suitable diluents include, but are not limited to, calcium carbonate, magnesium carbonate, magnesium oxide, sodium carbonate, lactose, microcrystalline cellulose, calcium phosphate, calcium hydrogen phosphate, sodium phosphate, Cellactose® 80 (75% alpha-lactose monohydrate and 25% cellulose powder), mannitol, pregelatinized starch, starch, sucrose, sodium chloride, talc, lactose anhydrous, and granulated lactose. One or more diluents may each be present individually in the composition in an amount of about 0.01% w / w to about 90% w / w by weight of the dosage form. One or more diluents may be present in the composition in an amount of greater than, greater than, or less than about 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% w / w by weight of the dosage form.

[0131] Suitable granulating and disintegrating agents include, but are not limited to, sucrose, copovidone, corn starch, microcrystalline cellulose, methylcellulose, sodium starch glycolate, pregelatinized starch, povidone, sodium carboxymethylcellulose, sodium alginate, citric acid, croscarmellose sodium, cellulose, calcium carboxymethylcellulose, colloidal silicon dioxide, crospovidone, and alginic acid. One or more granulating or disintegrating agents may each be present individually in the composition in an amount of about 0.01% w / w to about 90% w / w by weight of the dosage form. One or more granulating or disintegrating agents may each be present in the composition individually in an amount of greater than, greater than, or less than about 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% w / w by weight of the dosage form.

[0132] Suitable binders include, but are not limited to, gelatin, gum arabic, pregelatinized maize starch, polyvinylpyrrolidone, lactose anhydrous, lactose monohydrate, hydroxypropyl methylcellulose, methylcellulose, povidone, polyacrylamide, sucrose, glucose, maltose, gelatin, polyethylene glycol. One or more binders may be present in the composition, each individually, in an amount of about 0.01% w / w to about 90% w / w by weight of the dosage form. One or more binders may be present in the composition in an amount of greater than, greater than, or less than about 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% w / w by weight of the dosage form.

[0133] Suitable lubricants include, but are not limited to, magnesium stearate, calcium stearate, hydrogenated castor oil, glyceryl monostearate, glyceryl behenate, mineral oil, polyethylene glycol, poloxamer 407, poloxamer 188, sodium laureth sulfate, sodium benzoate, stearic acid, sodium stearyl fumarate, silica, and talc. One or more lubricants may each be present in the composition individually in an amount of about 0.01% w / w to about 90% w / w by weight of the dosage form. One or more lubricants may be present in the composition in an amount of greater than, greater than, or less than about 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% w / w by weight of the dosage form.

[0134] The tablet may be uncoated or may be coated using known methods to achieve delayed disintegration in the subject's gastrointestinal tract, thereby achieving sustained release and absorption of the active ingredient. For example, the tablet may be coated using materials such as glyceryl monostearate or glyceryl distearate. Furthermore, the tablet may be coated using methods described in, for example, U.S. Patent Nos. 4,256,108; 4,160,452; and 4,265,874 to form an osmotically controlled release tablet. The tablet may further include a sweetener, a flavoring agent, a coloring agent, a preservative, or any combination thereof to provide a pharma-ceutical elegant and palatable preparation.

[0135] The tablets may be enteric coated such that the coating begins to dissolve at a particular pH, e.g., from about pH 5.0 to about pH 7.5, thereby releasing the compounds described herein. The coating may include, for example, EUDRAGIT® L, S, FS, and / or E polymers having acidic or alkaline groups to allow release of the compounds described herein at a particular location, including any desired compartment of the intestine. The coating may include, for example, EUDRAGIT® RL and / or RS polymers having cationic or neutral groups to allow time-controlled release of the compounds described herein by pH-independent swelling.

[0136] Parenteral Administration For parenteral administration, the compounds described herein can be formulated for injection or infusion, e.g., intravenous, intramuscular, or subcutaneous injection or infusion, or for administration in a bolus dose and / or continuous infusion. Suspensions, solutions, or emulsions in oily or aqueous vehicles, which may contain other formulating agents such as suspending agents, stabilizing agents, and / or dispersing agents, can be used.

[0137] Sterile injectable forms of the compositions described herein may be aqueous or oleaginous suspensions. These suspensions can be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations may also be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, for example as a solution in 1,3-butanediol. Acceptable vehicles and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. Sterile fixed oils are usually used as solvents or suspending media. For this purpose, any bland fixed oil can be used, including synthetic mono- or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are pharma-ceutically acceptable natural oils, such as olive oil or castor oil, especially their polyoxyethylated versions. These oily solutions or suspensions may contain long-chain alcohol diluents or dispersants, such as lauryl, stearyl, or oleyl alcohol, or similar alcohols.

[0138] Further dosage forms Additional dosage forms suitable for use with the compounds and compositions described herein include those described in U.S. Patent Nos. 6,340,475; 6,488,962; 6,451,808; 5,972,389; 5,582,837; and 5,007,790. Additional dosage forms suitable for use with the compounds and compositions described herein also include those described in U.S. Patent Application Publication Nos. 20030147952; 20030104062; 20030104053; 20030044466; 20030039688; and 20020051820. Additional suitable formulations for use with the compounds and compositions described herein include those described in PCT Application Nos. WO 03 / 35041; WO 03 / 35040; WO 03 / 35029; WO 03 / 35177; WO 03 / 35039; WO 02 / 96404; WO 02 / 32416; WO 01 / 97783; WO 01 / 56544; WO 01 / 32217; WO 98 / 55107; WO 98 / 11879; WO 97 / 47285; WO 93 / 18755; and WO 90 / 11757.

[0139] Controlled Release Formulations and Drug Delivery Systems In certain embodiments, the formulations described herein can be, but are not limited to, short-term release formulations, rapid release formulations, and controlled release formulations, including sustained release formulations, delayed release formulations, slow release formulations, and pulsatile release formulations.

[0140] The term sustained release is used in its ordinary sense to refer to a drug formulation that gradually releases drug over an extended period of time and that can, but does not necessarily, result in substantially constant blood levels of drug over an extended period of time, which can be as long as a month or more and should be a longer release than the same amount of material administered in bolus form.

[0141] For sustained release, the compound can be formulated with suitable polymer or hydrophobic material that provides sustained release to the compound.Therefore, the compound used in the methods described herein can be administered in the form of microparticles, for example, by injection, or in the form of wafer or disk, by implantation.

[0142] In some cases, the dosage form used can be realized as slow release or controlled release of one or more active ingredients in the dosage form, for example, by using hydropropylmethylcellulose, other polymer matrices, gels, osmotic membranes, osmotic systems, multi-layer coatings, microparticles, liposomes, or microspheres, or their combinations in various ratios to achieve desired release profile.Suitable controlled release formulations known to those skilled in the art, including those described herein, can be easily selected for use in the pharmaceutical compositions described herein.Therefore, the single unit dosage form suitable for oral administration, such as tablets, capsules, gel capsules, and caplets, which are adapted for controlled release, are included in the compositions and dosage forms described herein.

[0143] Most controlled release formulations have a common goal of improving drug therapy compared to that achieved by the corresponding non-controlled formulation.Ideally, the use of an optimally designed controlled release formulation in medical treatment is characterized by a minimum amount of drug substance used to cure or control a condition in a minimum amount of time.The advantages of controlled release formulations include prolonged drug activity, reduced dosing frequency, and increased patient compliance.In addition, controlled release formulations can be used to affect the onset of action or other characteristics such as blood levels of the drug, and therefore can affect the occurrence of side effects.

[0144] Most controlled release formulations are designed to initially release an amount of drug that rapidly produces the desired therapeutic effect, and then slowly and continuously release other amounts of drug that maintain this level of therapeutic effect over an extended period of time. To maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that will replace the amount of drug being metabolized and excreted from the body.

[0145] The controlled release of active ingredient can be stimulated by various inducers, such as pH, temperature, enzymes, water, or other physiological conditions or compounds. The term "controlled release component" is defined herein as a compound including, but not limited to, a polymer, a polymer matrix, a gel, a permeable membrane, a liposome or a microsphere, or a combination thereof that facilitates the controlled release of active ingredient. In one embodiment, the compound described herein is administered to a patient alone or in combination with another agent using a sustained release formulation. In one embodiment, the compound described herein is administered to a patient alone or in combination with another agent using a sustained release formulation.

[0146] The term delayed release is used herein in its ordinary sense to refer to a drug formulation that provides for initial release of drug after some delay following drug administration, which may include, but is not necessarily, a delay of from about 10 minutes to about 12 hours.

[0147] The term pulsatile release is used herein in its ordinary sense to refer to a drug formulation that provides release of drug in a manner that results in a pulsatile plasma profile of the drug following drug administration.

[0148] The term immediate release is used in its ordinary sense to refer to a drug formulation that provides for release of drug immediately following drug administration.

[0149] Short term, as used herein, means any period of time up to about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes, or about 10 minutes, and any integer or non-integer units therebetween.

[0150] As used herein, rapidly means any period of time up to about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes, or about 10 minutes after drug administration, and any integer or non-integer units therebetween.

[0151] Administration The therapeutically effective amount or dose of the compounds described herein depends on the age, sex, and weight of the patient, the current medical condition of the patient, and the progression of AUD or anxiety in the patient being treated. Those skilled in the art can determine the appropriate dosage depending on these and other factors.

[0152] Suitable doses of the compounds described herein may range from about 0.01 mg to about 5,000 mg per day, for example, from about 0.1 mg to about 1,000 mg per day, for example, from about 1 mg to about 500 mg, for example, from about 5 mg to about 250 mg. Doses can be administered in single or multiple doses, for example, from 1 to 4 or more times per day. When multiple doses are used, the amount in each dose can be the same or different. For example, a 1 mg dose per day can be administered as two 0.5 mg doses, with an interval of about 12 hours between the doses.

[0153] It will be understood that the amount of compound administered per day can be administered, in non-limiting examples, every day, every other day, every second day, every third day, every fourth day, or every fifth day. For example, for every other day administration, a dose of 5 mg per day can be administered starting on Monday, a first subsequent dose of 5 mg per day can be administered on Wednesday, and a second subsequent dose of 5 mg per day can be administered on Friday.

[0154] If the patient's condition improves, at the physician's discretion, administration of the compounds described herein may continue, or the dose of the drug administered may be temporarily reduced or temporarily discontinued for a period of time (i.e., a "drug holiday"). The length of the drug holiday may vary anywhere from 2 days to 1 year, and includes, by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days. Dose reductions during drug holidays include 10% to 100%, by way of example only 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.

[0155] When improvement of the patient's condition occurs, a maintenance dose is administered if necessary. The dosage or frequency of administration, or both, is then reduced to a level at which improvement in the disease is maintained. In certain embodiments, the patient may require long-term intermittent treatment for any recurrence of symptoms and / or infection.

[0156] The compounds described herein can be formulated in unit dosage form. The term "unit dosage form" refers to a physically discrete unit suitable as a unitary dosage form for a patient to be treated, each unit containing a predetermined amount of active agent calculated to produce a desired therapeutic effect, optionally in combination with a suitable pharmaceutical carrier. The unit dosage form can be for a single daily administration, or for one of multiple daily administrations (e.g., about 1-4 or more times per day). When multiple daily administrations are used, the unit dosage form can be the same or different for each administration.

[0157] The toxicity and therapeutic efficacy of the treatment regimen in question are optionally determined in cell culture or experimental animals, and the LD 50 (a dose lethal to 50% of the population) and ED 50These include, but are not limited to, determining the dose that is therapeutically effective in 50% of the population. The dose ratio between toxic and therapeutic effects is the therapeutic index, which is the LD 50 and ED 50 The data obtained from cell culture assays and animal studies may be used in formulating a range of dosages for use in humans. The dosage of the compound is determined to be sufficient to achieve the ED with minimal toxicity. 50 It is preferred that the dosage form be within a circulating concentration range that includes the active ingredient, the active ingredient, and the active ingredient(s) in the formulation. The dosage can optionally vary within this range depending upon the dosage form employed and the route of administration utilized. EXAMPLES

[0158] Various aspects of the present application can be better understood with reference to the following examples, which are provided by way of illustration and are not intended to limit the scope of the present application.

[0159] Example 1: Synthesis of 6-bromo-3,3-bis(hydroxymethyl)-2-phenylchroman-4-one TIFF2024538721000024.tif27148Scheme 5: a) NBS, MeOH, oxone, b) HCHO, MeOH, Na2CO

[0160] 6-Bromo-3,3-bis(hydroxymethyl)-2-phenylchroman-4-one 2-Phenyl-2,3-dihydrochromen-4-one (223 mg, 1.0 mmol) was dissolved in 1:1 acetone:water (10 mL). Hydrogen oxydosulfate (152 mg, 1.0 mmol, 1 equiv) and NaBr (206 mg, 2.0 mmol, 2 equiv) were added and the reaction was stirred at room temperature for 36 h. The reaction was then quenched with water, extracted with ethyl acetate (2x50 mL) and dried under reduced pressure. The final product was isolated by silica gel flash column chromatography with a solvent gradient of 0-10% ethyl acetate / hexane to give 6-bromo-3,3-bis(hydroxymethyl)-2-phenylchroman-4-one (95 mg, 0.31 mmol, 31% yield). 6-Bromo-3,3-bis(hydroxymethyl)-2-phenylchroman-4-one was dissolved in acetonitrile (10 mL). Na2CO3 (59 mg, 0.56 mmol, 4 equiv) and formaldehyde (37% w / v aqueous solution, 0.5 mL, 0.56 mmol, 4 equiv) were added and the reaction was stirred at room temperature for 48 h. The reaction was then quenched with water, extracted into ethyl acetate, dried over Na2SO4, filtered, and evaporated to dryness. The final product was isolated using a C-18 flash column and a solvent gradient of 5-60% acetonitrile / water containing 0.1% formic acid to give C1 (21.3 mg, 0.05 mmol, 26% yield). TIFF2024538721000025.tif41160

[0161] Example 2: Synthesis of 3,3-bis(hydroxymethyl)-2-(3-nitrophenyl)chroman-4-one TIFF2024538721000026.tif34170 Scheme 6: a) MeOH, KOH, b) KOH, MeOH, c) HCHO, Na2CO3, EtOH

[0162] 1-(5-Bromo-2-hydroxyphenyl)ethan-1-one (1 eq, 951 mg, 4.4 mmol) was dissolved in 1:1 THF / ethanol. 5 eq of NaOH (2M) was slowly added and the reaction was stirred at room temperature for 15 min. 3-Nitrobenzaldehyde (1.2 eq, 798 mg, 5.3 mmol) was added and the reaction was stirred at room temperature for 48 h. The reaction was then quenched with water, extracted into ethyl acetate, and dried under reduced pressure. 3-Nitro-2-phenylchromen-4-one was isolated by silica gel column chromatography using a solvent gradient of 10-25% ethyl acetate / hexane (yield = 45%). 3-Nitro-2-phenylchromen-4-one (104 mg, 0.3 mmol) was then dissolved in ethanol (10 mL). Na2CO3 (59 mg, 0.56 mmol, 4 equiv) and formaldehyde (37% w / v aqueous solution, 0.5 mL, 0.56 mmol, 4 equiv) were added and the reaction was stirred at room temperature for 48 h. The reaction was then quenched with water, extracted into ethyl acetate, dried over Na2SO4, filtered, and evaporated to dryness. The final product was isolated on a silica gel column with a solvent gradient of 10-25% ethyl acetate / hexanes (52 mg, 0.13 mmol, 56% yield). TIFF2024538721000027.tif34158

[0163] Example 3: Synthesis of 6-bromo-2-(3-nitrophenyl)-2,3-dihydroquinazolin-4(1H)-one TIFF2024538721000028.tif31128Scheme 7: a) Ethanol, CuI, 2 hours, room temperature

[0164] 6-Bromo-2-(3-nitrophenyl)-2,3-dihydroquinazolin-4(1H)-one 3-Nitrobenzaldehyde (1.2 equiv., 109 mg, 0.7 mmol) and 2-amino-5-bromobenzamide (1 equiv., 130 mg, 0.6 mmol) were dissolved in ethanol (10 mL) with a catalytic amount of CuI (~1 mg) and stirred at room temperature for 2 h. The reaction was then diluted with water, extracted into ethyl acetate, and dried under reduced pressure. 6-Bromo-2-(3-nitrophenyl)-2,3-dihydroquinazolin-4(1H)-one (C5) was isolated by silica gel column chromatography with a solvent gradient of 25-100% ethyl acetate / hexane. The final product gave a yellow crystalline material (yield = 39%, 82 mg, 0.2 mmol). TIFF2024538721000029.tif27155

[0165] Example 4: Synthesis of 6-bromo-2-(3-nitrophenyl)-2,3-dihydro-4H-benzo[e][1,3]oxazin-4-one TIFF2024538721000030.tif36141Scheme 8: a) Toluene, piperidine, 100°C for 72 hours.

[0166] EC2-118 was crystallized from solution and filtered to give a 30% isolated yield. TIFF2024538721000031.tif20155Figure 6 shows the HPLC-UV-MS / MS analysis of EC2-118.

[0167] 6-Bromo-2-(3-nitrophenyl)-2,3-dihydro-4H-benzo[e][1,3]oxazin-4-one 3-Nitrobenzaldehyde (1.5 equiv., 1200 mg, 7.9 mmol) and 5-bromo-2-hydroxybenzamide (1 equiv., 1150 mg, 5.3 mmol) were dissolved in toluene (100 mL). Piperidine (0.35 equiv., 1.3 mmol) was added and the reaction was refluxed at 100 °C for 6 h. The reaction was then diluted with water, extracted with ethyl acetate, and dried under reduced pressure. The final product was isolated by silica gel column chromatography with a solvent gradient of 25-100% ethyl acetate / hexane to give a white crystalline product (yield = 29%, 550 mg, 1.6 mmol). TIFF2024538721000032.tif27159

[0168] Example 5: Native GABA A Screening for R activity As part of the screening model, a total of seven molecules were analyzed, including (R)-dihydromyricetin (a natural flavanol), 6-bromo-3'-nitroflavone (a commercially available synthetic flavone), and the molecular compounds (EC2-52, EC2-104, EC2-117, EC2-118, and EC2-124) (Scheme 9). To confirm this activity, 6-bromo-3'-nitroflavone, a known strong competitive binder for the BZD binding site of GABAARs with low intrinsic efficacy, was included.

[0169] TIFF2024538721000033.tif65146 Scheme 9: Structures and names of the compounds analyzed

[0170] As used herein, the compounds of Scheme 9 also have the following alternative names: EC2-52 (Compound C1), EC2-104 (Compound C2), EC2-117 (Compound 5 and its tautomers), EC2-118 (Compound 4 and its tautomers), and EC2-124 (Compound C3).

[0171] Subtype-specific GABA A Electrophysiological studies in Xenopus oocytes expressing the receptor α5β3γ2 GABA AElectrophysiological studies were performed in Xenopus oocytes expressing R. Xenopus oocytes were stored in incubation medium (pH 7.5) consisting of ND96 supplemented with 2 mM sodium pyruvate, 0.1 nM gentamicin, and 10 mL of heat-inactivated HyClone horse serum. Stage 4–5 oocytes were injected with 40 nL of cDNA encoding the α5, β3, and γ2 subunits in a 1:1:10 ratio using a Drummond Nanoject III. Injected oocytes were stored at 18°C ​​and used for electrophysiological studies within 2–7 days after injection. Whole-cell two-electrode voltage clamp (TEVC) recordings were performed on oocytes in the presence of GABA. Oocytes were voltage clamped at a membrane potential of -70 mV. Oocyte recording chambers were continuously perfused with modified bath solution (MBS) at a final concentration of 1% DMSO with selected compounds (10 μM) and GABA (10 μM). It has been previously demonstrated that this DMSO concentration did not significantly affect GABAAR function. Oocytes were perfused at a rate of 3 mL / min. Electrophysiological recordings were performed in triplicate for each compound. GABA A The change in R activity was measured using EC 20 GABA A R enhancement was determined by comparison with control saline in the presence of GABA. Statistical significance was determined. Statistical significance of electrophysiological results of compound GABAergic modulation was determined using paired t-tests (vehicle control vs. compound, GraphPad software, San Diego, CA, USA). P<0.05 was considered significant.

[0172] To assess potential anxiolytic activity, compounds were tested using electrophysiological tests to assess in vitro GABAergic activity. A The study was performed to screen for GABA receptor activity, which has known anxiolytic activity. A It is an established method to evaluate the activity of receptor positive allosteric modulators (PAMs). APrevious studies have also established an association between anxiolytic and sedative activity associated with the R subtype, and the potential of full GABA receptor antagonists in the treatment of anxiety and seizure disorders. A R A history of clinical effectiveness, benefits, and risks associated with the use of PAMs [i.e., benzodiazepines (BZDs)] is well established.

[0173] GABA A To assess receptor activity, compounds were administered to four GABA receptors in positive allosteric modulator (PAM) mode using the SyncroPatch automated platform at room temperature. A Subtype (GABA A The activity of the α1β2γ2L, α2β3γ2L, α5β3γ2L, and α4β3δ receptors was assessed by electrophysiological testing. Six-point concentration-response curves for each test compound (10, 1, 0.1, 0.01, 0.001, or 0.0001 μM in DMSO). A rapid addition protocol was used in which compounds were applied immediately and then washed off from the cells. 0.3% DMSO was used as a negative control.

[0174] The assay was performed as follows.

[0175] Concentration and replicate data Test compounds: Six point concentration response curves for each test compound (10, 1, 0.1, 0.01, 0.001, 0.0001 μM in DMO). Positive control: a five-point concentration-response curve of allopregnanolone (10, 1, 0.1, 0.01, 0.01 μM). Negative control: 0.3% DMSO Each compound is tested at one concentration per cell across the plate. A minimum of two wells are obtained per concentration. keep: Powder and DMSO stocks are stored at room temperature (in the dark). On the day of the experiment, powder stocks are diluted to 3 mM in 100% DMSO. solution: SyncroPatch specific solutions are used throughout the assay. DMSO remains constant at 0.3% in the external solution throughout the assay. Applicable protocols: A rapid addition protocol is used where compounds are applied quickly and then washed off from the cells. To test PAM activity, the agonist GABA EC10-20 is applied three times (with a wash step in between) as a control, followed by a 1-2 min preincubation of client compound to demonstrate reproducibility of activation, and then GABA EC10-20 is reapplied in the presence of client compound. A further wash step is followed by a maximum amount of GABA (10 mM). analysis: Automated patch clamp recordings are performed using SyncroPatch 384i. Voltage protocol generation and data acquisition are performed by PatchController384 V1.9.0 and Data Controller V1.9.0.

[0176] The increase rate is expressed by the formula (I comp / I control )-1, wherein I comp is the current amplitude in the presence of compound, I control is the current amplitude in the presence of agonist alone. This gives the EC 50 Concentration response curves are constructed, where 0 represents no PAM activity and >0 represents PAM activity. If a "bell curve" is observed at higher concentrations, indicating decreased activity compared to previous concentrations, these concentrations are removed from the graph as necessary to make the curve fitting more accurate and noted in the compound table. % E for allopregnanolone max Formula [(I MaxComp / I AveMaxCtrl )*100], where I MaxComp is the individual maximum increase in current for each compound, and I AveMaxCtrl is the average maximum fold increase produced in the presence of the control, allopregnanolone.

[0177] To test PAM activity, the agonist GABA EC10-20 was applied three times (with wash steps in between) as a control, followed by pre-incubation of client compound for 1-2 min to demonstrate reproducibility of activation, and then GABA EC10-20 was reapplied in the presence of client compound. A maximum amount of GABA (10 mM) was applied after a further wash step. Allopregnanolone was utilized as a positive control. Figure 5A and Figure 5B show a comparison of the dose response of EC2-118 to that of allopregnanolone (positive control).

[0178] Table 1. Electrophysiological results for compounds EC2-52, EC2-104, EC2-117, EC2-118, and EC2-124 TIFF2024538721000034.tif199164a) *Expressed as EC50 or *IC50 (nM). Subtype-specific data are shown where available.

[0179] Example 6: In vivo anxiolytic and sedative activity by IP administration In vivo studies in rats were performed at Bello Laboratory as a preliminary screening of the activity of EC2-118. Male and female rats were subjected to the open field test (OFT) and the elevated plus maze test (EPM) 7 days apart (Kshatriya et al., 2020). Each group (n = 8 / group, total = 24) received an IP injection 30 minutes before IP administration of EC2-118 or vehicle control. We performed OFT and EPM in 52 adult SD rats (26 males / 26 females). The groups were as follows: vehicle (0.9% saline, 4% Tween 80, and 4% DMSO; male n = 9; female n = 10), 3.95 mg / kg (male n = 10; female n = 8), 12.5 mg / kg (male n = 7, female n = 8). Statistical analysis was completed using a two-way ANOVA with treatment and sex as factors and showed significant differences between the 3.95 mg / kg dose and the vehicle control (Figure 7).

[0180] Rats were administered EC2-118 (3.95 mg / kg IP) and alcohol (3 g / kg) and the duration of loss of righting reflex (LORR) was evaluated. RUEC2-118 (3.95 mg / kg, 12.95 IP) did not induce LORR. Furthermore, EC2-118 3.95 mg / kg showed no significant effect on alcohol-induced LORR. The effect of EC2-118 (12.5 mg / kg IP) on alcohol-induced LORR was not determined.

[0181] In summary, the compound of formula I showed statistically significant anxiolytic effects in male and female rats at a dose of 3.95 mg / kg IP. A dose of 12.5 mg / kg EC2-118 IP showed no significant effects in the open field test (OFT), but increased lethargy was observed at 12.5 mg / kg IP along with enhanced motor impairment at 12.5 mg / kg IP (as evidenced by the rotarod test), suggesting that GABA A This suggests a dose-dependent increase in sedative effect as would be expected for R PAM.

[0182] The terms and expressions used in this specification are used as terms of description and not of limitation, and in the use of these terms and expressions, there is no intention to exclude any equivalents of the features shown and described or portions thereof, and it will be recognized that various modifications are possible within the scope of the aspects of this application. Thus, although specific embodiments and optional features are described in this application, it should be understood that those skilled in the art may resort to modifications and / or variations of the compositions, methods, and concepts disclosed herein, and that these modifications and variations are considered to be within the scope of the aspects of this application.

[0183] Numbered Aspects The following numbered aspects are presented, however, the numbering should not be construed as indicating any level of importance.

[0184] Embodiment 1 provides a compound of formula I, or a salt, solvate, tautomer, enantiomer, diastereoisomer, and / or isotopically labeled derivative thereof: TIFF2024538721000035.tif34128In formula, TIFF2024538721000036.tif2128 is independently a single or double bond in each occurrence, and the XC* and GC* bonds are If the XC* bond is a double bond, The GC* bond is a single bond, and X is N, or If the XC* bond is a single bond, The GC* bond is a single or double bond, and X is O, NR, or S Selected to be; Each occurrence of Y is independently R, F, Cl, Br, I, OR, CN, NO2, N(R)2, SR, S(=O)R, SF3, SF5, S(=O)2R, S(=O)2N(R)2, P(=O)OH2, P(=O)OR2, C(=O)R, C(=O)OR, C(=O)N(R)2, OC(=O)R, OC(=O)N(R)2, C 3~10 Heterocycloalkyl, and C 5~10 is heteroaryl; G is C or N, If G is N or the GC* bond is a double bond, Z 2 and R 2 does not exist; A is C 6~10 Aryl or C 5~10 heteroaryl, each of which is optionally substituted with 1 to 5 substituents independently selected from the group consisting of R, F, Cl, Br, I, OR, CN, NO2, N(R)2, SR, S(=O)R, SF3, SF5, S(=O)2R, S(=O)2N(R)2, P(=O)OH2, P(=O)OR2, C(=O)R, C(=O)OR, C(=O)N(R)2, OC(=O)R, and OC(=O)N(R)2; Z 1 and Z 2is independently at each occurrence O, CH2, CHF, or CF2; R 1 and R 2 is independently OR, SR, or R in each occurrence; Or, -(Z 1 ) n1 -R 1 is H, Or, -(Z 2 ) n2 -R 2 is H, Each occurrence of R is hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~8 Cycloalkyl, C 3~8 Cycloalkenyl, and C 3~8 independently selected from the group consisting of halocycloalkyl; n is 1, 2, 3, 4, or 5; n1 is 1, 2, or 3; n2 is 1, 2, or 3.

[0185] Aspect 2 is The compound of embodiment 1 is provided, which is TIFF2024538721000037.tif71148.

[0186] Aspect 3 is The compound according to any one of embodiments 1 to 2 is provided, which is TIFF2024538721000038.tif35128.

[0187] Aspect 4 provides a compound of any of aspects 1-3, wherein X is O.

[0188] Embodiment 5 provides a compound of any of embodiments 1-4, wherein G is C.

[0189] Aspect 6 is Z 1 and Z 2 is CH2.

[0190] Embodiment 7 provides a compound of any of embodiments 1-6, wherein n1 and n2 are 1.

[0191] Aspect 8 is R 1 and R 2 The compound of any of embodiments 1-7 is provided, wherein is OH.

[0192] In the ninth aspect, A is TIFF2024538721000039.tif11128, p is an integer from 1 to 5; Q is selected from the group consisting of F, Cl, Br, I, OR, CN, NO2, N(R)2, SR, S(=O)R, SF3, SF5, S(=O)2R, S(=O)2N(R)2, P(=O)OH2, P(=O)OR2, C(=O)R, C(=O)OR, C(=O)N(R)2, OC(=O)R, and OC(=O)N(R); R is hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~8 Cycloalkyl, C 3~8 Cycloalkenyl, and C 3~8 The compound of any of embodiments 1-8 is provided, wherein the compound is independently selected from the group consisting of halocycloalkyl.

[0193] Embodiment 10 provides a compound of any of embodiments 1-9, wherein Y is F, Cl, Br, or I.

[0194] Embodiment 11 provides a compound of any of embodiments 1-10, wherein Y is Br.

[0195] Aspect 12 is an embodiment in which G is N and Z 1 is H and R 1 The compound of any of embodiments 1-11 is provided, wherein is absent.

[0196] Aspect 13 is a method for producing The compound of any one of embodiments 1 to 12 is provided, which is TIFF2024538721000040.tif53153.

[0197] Aspect 14 is a method for producing The compound of any one of embodiments 1 to 13 is provided, which is TIFF2024538721000041.tif15128.

[0198] Aspect 15 is a method for producing a The present invention provides a compound selected from the group consisting of: TIFF2024538721000042.tif53133.

[0199] Embodiment 16 provides a pharmaceutical composition comprising a compound of any of embodiments 1-15 and at least one pharma- ceutically acceptable carrier.

[0200]

[0023] Embodiment 17 provides a method of treating, ameliorating, and / or preventing alcohol use disorder (AUD) in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula I, or a salt, solvate, tautomer, enantiomer, diastereoisomer, and / or isotopically labeled derivative thereof: TIFF2024538721000043.tif34128 formula, TIFF2024538721000044.tif2128 is independently a single bond or a double bond in each occurrence; Each occurrence of Y is independently R, F, Cl, Br, I, OR, CN, NO2, N(R)2, SR, S(=O)R, SF3, SF5, S(=O)2R, S(=O)2N(R)2, P(=O)OH2, P(=O)OR2, C(=O)R, C(=O)OR, C(=O)N(R)2, OC(=O)R, OC(=O)N(R)2, C 3~10 Heterocycloalkyl, and C 5~10 is heteroaryl; X is O, N, NR, or S; G is C or N, and if G is N, Z 2 and R 2 does not exist; A is C 6~10 Aryl or C5~10 heteroaryl, each of which is optionally substituted with 1 to 5 substituents independently selected from the group consisting of R, F, Cl, Br, I, OR, CN, NO2, N(R)2, SR, S(=O)R, SF3, SF5, S(=O)2R, S(=O)2N(R)2, P(=O)OH2, P(=O)OR2, C(=O)R, C(=O)OR, C(=O)N(R)2, OC(=O)R, and OC(=O)N(R)2; Z 1 and Z 2 is independently at each occurrence H, O, CH2, CHF, or CF2; R 1 and R 2 each independently is absent, H, OR, SR, or R; Each occurrence of R is hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~8 Cycloalkyl, C 3~8 Cycloalkenyl, and C 3~8 independently selected from the group consisting of halocycloalkyl; n is 1, 2, 3, 4, or 5; n1 is 1, 2, or 3; n2 is 1, 2, or 3.

[0201] Example 18 provides the method of Example 17, wherein the alcohol use disorder comprises alcoholism.

[0202] Aspect 19 provides the method of any of Aspects 17-18, wherein the compound is formulated as a pharmaceutical composition further comprising at least one pharma- ceutically acceptable carrier.

[0203] Aspect 20 is a compound comprising 20. The method of any one of Aspects 17 to 19, wherein the image is TIFF2024538721000045.tif71148.

[0204] Aspect 21 is a compound comprising The method according to any one of aspects 17 to 20 is provided, wherein the image is TIFF2024538721000046.tif36128.

[0205] Example 22 provides the method of any of Examples 17-21, wherein X is O.

[0206] Aspect 23 is Z 1 and Z 2 is CH2.

[0207] Example 24 provides the method of any of Examples 17 to 23, wherein n1 and n2 are 1.

[0208] Aspect 25 is R 1 and R 2 is OH.

[0209] Aspect 26 is a compound according to claim 1, wherein A is TIFF2024538721000047.tif11128, p is an integer from 1 to 5; Q is selected from the group consisting of F, Cl, Br, I, OR, CN, NO2, N(R)2, SR, S(=O)R, SF3, SF5, S(=O)2R, S(=O)2N(R)2, P(=O)OH2, P(=O)OR2, C(=O)R, C(=O)OR, C(=O)N(R)2, OC(=O)R, and OC(=O)N(R); R is hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~8 Cycloalkyl, C 3~8 Cycloalkenyl, and C 3~8 26. The method of any of embodiments 17-25, wherein the aryl group is independently selected from the group consisting of halocycloalkyl.

[0210] Aspect 27 is a method for producing The method according to any one of aspects 17 to 26 is provided, wherein the image is TIFF2024538721000048.tif53152.

[0211] In aspect 28, A is The method of any one of aspects 17 to 27 is provided, wherein the image is TIFF2024538721000049.tif15128.

[0212] Example 29 provides the method of any of Examples 17-28, wherein Y is F, Cl, Br, or I.

[0213] Example 30 provides the method of any of Examples 17-29, wherein Y is Br.

[0214] Aspect 31 is directed to a compound comprising: The method according to any one of aspects 17 to 30 is provided, wherein the nucleic acid sequence is selected from the group consisting of: TIFF2024538721000050.tif53133.

[0215] Example 32 provides the method of any of Examples 17 to 31, wherein the subject is a mammal.

[0216] Embodiment 33 provides the method of any of embodiments 17 to 32, wherein the mammal is a human.

[0217] Embodiment 34 provides the method of any of embodiments 17-33, wherein at least one additional agent for treating, ameliorating, and / or preventing AUD is further administered to the subject.

[0218] Aspect 35 provides the method of any of Aspects 17-34, wherein the compound is administered by a route selected from the group consisting of oral, transdermal, transmucosal, intravesical, intrapulmonary, intraduodenal, intragastric, intrathecal, subcutaneous, intramuscular, intradermal, intraarterial, intravenous, intrabronchial, inhalation, and topical administration.

[0219] Aspect 36 provides the method of any of Aspects 17 to 35, wherein the route is oral administration.

Claims

1. A compound of formula I, or a salt, solvate, tautomer, enantiomer, diastereoisomer, and / or isotopically labeled derivative thereof: During the ceremony, is independently a single or double bond in each occurrence, and the XC* and GC* bonds are If the XC* bond is a double bond, The GC* bond is a single bond, and X is N, or If the XC* bond is a single bond, The GC* bond is a single or double bond, and X is O, NR, or S Selected as; Each occurrence of Y is independently R, F, Cl, Br, I, OR, CN, NO 2 , N(R) 2 , SR, S(=O)R, SF 3 ,SCIENCE FICTION 5 , S(=O) 2 R, S(=O) 2 N(R) 2 , P(=O)OH 2 , P(=O)OR 2 , C(=O)R, C(=O)OR, C(=O)N(R) 2 , OC(=O)R, OC(=O)N(R) 2 , C 3～10 Heterocycloalkyl, and C 5～10 is heteroaryl; G is C or N, If G is N or the GC* bond is a double bond, Z 2 and R 2 does not exist; A is C 6～10 Aryl or C 5～10 Heteroaryl is R, F, Cl, Br, I, OR, CN, or NO 2 , N(R) 2 , SR, S(=O)R, SF 3 ,SCIENCE FICTION 5 , S(=O) 2 R, S(=O) 2 N(R) 2 , P(=O)OH 2 , P(=O)OR 2 , C(=O)R, C(=O)OR, C(=O)N(R) 2 , OC(=O)R, and OC(=O)N(R) 2 and optionally substituted with 1 to 5 substituents independently selected from the group consisting of: Z 1 and Z 2 is independently O, CH 2 , CHF, or CF 2 and; R 1 and R 2 is independently OR, SR, or R in each occurrence; Alternatively, -(Z 1 ) n1 -R 1 is H, Alternatively, -(Z 2 ) n2 -R 2 is H, Each occurrence of R is hydrogen, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, C 1～6 Haloalkyl, C 3～8 Cycloalkyl, C 3～8 Cycloalkenyl, and C 3～8 independently selected from the group consisting of halocycloalkyl; n is 1, 2, 3, 4, or 5; n1 is 1, 2, or 3; n2 is 1, 2, or 3.

2. The compound of formula I, 2. The compound of claim 1, wherein:

3. The compound of formula I, 2. The compound of claim 1, wherein:

4. 2. The compound of claim 1, wherein X is O.

5. 2. The compound of claim 1, wherein G is C.

6. Z 1 and Z 2 is CH 2 2. The compound of claim 1, wherein:

7. 2. The compound of claim 1, wherein n1 and n2 are 1.

8. R 1 and R 2 2. The compound of claim 1, wherein is OH.

9. A is and p is an integer from 1 to 5; Q is F, Cl, Br, I, OR, CN, NO 2 , N(R) 2 , SR, S(=O)R, SF 3 ,SCIENCE FICTION 5 , S(=O) 2 R, S(=O) 2 N(R) 2 , P(=O)OH 2 , P(=O)OR 2 , C(=O)R, C(=O)OR, C(=O)N(R) 2 , OC(=O)R, and OC(=O)N(R) 2 selected from the group consisting of: R is hydrogen, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, C 1～6 Haloalkyl, C 3～8 Cycloalkyl, C 3～8 Cycloalkenyl, and C 3～8 2. The compound of claim 1, wherein each of said aryl groups is independently selected from the group consisting of halocycloalkyl.

10. 2. The compound of claim 1, wherein Y is F, Cl, Br, or I.

11. 11. The compound of claim 10, wherein Y is Br.

12. G is N and Z 1 is H and R 1 2. The compound of claim 1, wherein:

13. A is 10. The compound of claim 9, wherein:

14. A is 2. The compound of claim 1, wherein:

15. The compound of formula I, 2. The compound of claim 1, selected from the group consisting of:

16. 10. A pharmaceutical composition comprising the compound of claim 1 and at least one pharmaceutically acceptable carrier.

17. A pharmaceutical composition for use in treating, ameliorating, and / or preventing alcohol use disorder (AUD) in a subject, comprising a therapeutically effective amount of a compound of Formula I, or a salt, solvate, tautomer, enantiomer, diastereoisomer, and / or isotopically labeled derivative thereof: During the ceremony, is independently a single or double bond in each occurrence, and the XC* and GC* bonds are If the XC* bond is a double bond, The GC* bond is a single bond, and X is N, or If the XC* bond is a single bond, The GC* bond is a single or double bond, and X is O, NR, or S Selected as; Each occurrence of Y is independently R, F, Cl, Br, I, OR, CN, NO 2 , N(R) 2 , SR, S(=O)R, SF 3 ,SCIENCE FICTION 5 , S(=O) 2 R, S(=O) 2 N(R) 2 , P(=O)OH 2 , P(=O)OR 2 , C(=O)R, C(=O)OR, C(=O)N(R) 2 , OC(=O)R, OC(=O)N(R) 2 , C 3～10 Heterocycloalkyl, and C 5～10 is heteroaryl; G is C or N, If G is N or the GC* bond is a double bond, Z 2 and R 2 does not exist; A is C 6～10 Aryl or C 5～10 Heteroaryl is R, F, Cl, Br, I, OR, CN, or NO 2 , N(R) 2 , SR, S(=O)R, SF 3 ,SCIENCE FICTION 5 , S(=O) 2 R, S(=O) 2 N(R) 2 , P(=O)OH 2 , P(=O)OR 2 , C(=O)R, C(=O)OR, C(=O)N(R) 2 , OC(=O)R, and OC(=O)N(R) 2 and optionally substituted with 1 to 5 substituents independently selected from the group consisting of: Z 1 and Z 2 is independently O, CH 2 , CHF, or CF 2 and; R 1 and R 2 is independently OR, SR, or R in each occurrence; Alternatively, -(Z 1 ) n1 -R 1 is H, Alternatively, -(Z 2 ) n2 -R 2 is H, Each occurrence of R is hydrogen, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, C 1～6 Haloalkyl, C 3～8 Cycloalkyl, C 3～8 Cycloalkenyl, and C 3～8 independently selected from the group consisting of halocycloalkyl; n is 1, 2, 3, 4, or 5; n1 is 1, 2, or 3; n2 is 1, 2, or 3.

18. 18. The pharmaceutical composition of claim 17, wherein the alcohol use disorder comprises alcoholism.

19. The pharmaceutical composition of claim 17, wherein the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier.

20. The compound of formula I, 18. The pharmaceutical composition of claim 17, wherein the composition is selected from the group consisting of:

21. 18. The pharmaceutical composition of claim 17, wherein the subject is a mammal.

22. 22. The pharmaceutical composition of claim 21, wherein the mammal is a human.

23. 18. The pharmaceutical composition of claim 17, for use in combination with at least one additional agent for treating, ameliorating, and / or preventing AUD.

24. 18. The pharmaceutical composition of claim 17, wherein the pharmaceutical composition is administered by a route selected from the group consisting of oral administration, transdermal administration, transmucosal administration, intravesical administration, intrapulmonary administration, intraduodenal administration, intragastric administration, intrathecal administration, subcutaneous administration, intramuscular administration, intradermal administration, intraarterial administration, intravenous administration, intrabronchial administration, inhalation administration, and topical administration.

25. 25. The pharmaceutical composition of claim 24, wherein the route is oral administration.

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